Publications

Ocular hypertension, believed to result partly from increased contractile activity, cell adhesive interactions, and stiffness within the trabecular meshwork (TM), is a major risk factor for glaucoma, a leading cause of blindness. However, the identity of molecular mechanisms governing organization of actomyosin and cell adhesive interactions in the TM remains limited. Based on our previous findings, in which proteomics analyses revealed elevated levels of septins, including septin-9 in human TM cells treated with the ocular hypertensive agent dexamethasone, here, we evaluated the effects of septin-9 overexpression, deficiency, and pharmacological targeting in TM cells. These studies demonstrated a profound impact on actomyosin organization, cell adhesion, contraction, and phagocytosis. Overexpression raised intraocular pressure (IOP) in mice, while inhibition increased cell permeability. In addition, we replicated a significant association between a common variant (rs9038) in SEPT9 with IOP in the Genetic Epidemiology Research on Adult Healthy and Aging (GERA) cohort. Collectively, these data reveal a link between dysregulated septin cytoskeletal organization in the TM and increased IOP, likely due to enhanced cell contraction, adhesive interactions, and fibrotic activity. This suggests that targeting the septin cytoskeleton could offer a novel approach for lowering IOP in patients with glaucoma.

Authors: Maddala R; Gorijavolu P; Lankford LK; Skiba NP; Challa P; Singh RK; Nair KS; Choquet H; Rao PV | December 6, 2024 | PubMed abstract

The objective of this study was to examine the interplay of polygenic risk and individual lifestyle factors (and a composite score of lifestyle) as antecedents of CHD in a large multiethnic cohort. We used Genetic Epidemiology Resource in Adult Health and Aging (GERA) cohort participants free of CHD at baseline (n = 60,568; 67 % female; 18 % non-European). The individual and joint associations of smoking, Mediterranean diet pattern, level of physical activity and polygenic risk with incident CHD were assessed using Cox regression adjusting for genetic ancestry and non-mediating risk factors. Hazard ratios (HRs) and number needed to treat (NNT) were estimated according to these lifestyle factors and polygenic risk categories. Strengths included large sample size, long-follow-up, ethnic diversity, a clinically-validated polygenic risk score (PRS), and rich phenotype information. After 14 years of follow-up, there were 3159 incident CHD events. We observed no statistically significant interactions between individual lifestyle factors and polygenic risk (all p > 0.23). For individuals with a high genetic risk, moving from the worse lifestyle combination (no favorable lifestyle factors) to the best lifestyle combination (all three) is associated with 52 % lower rate of CHD. The NNT was highest in the low polygenic risk group (34), lowest in the high polygenic risk group [19] and in-between (Jin et al., 2011) [24] in the intermediate polygenic risk group. Lifestyle and polygenic risk together influence the risk of incident CHD. Our results support consideration of polygenic risk in lifestyle interventions because those with high polygenic risk are likely to derive the most benefit.

Authors: Iribarren C; Lu M; Gulati M; Wong ND; Elosua R; Rana JS | December 1, 2024 | PubMed abstract

Food is Medicine (FIM) interventions reflect the critical links between food security, nutrition security, health, and health equity, integrated into health care delivery. They comprise programs that provide nutritionally tailored food, free of charge or at a discount, to support disease management, disease prevention, or optimal health, linked to the health care system as part of a patient’s treatment plan. Such programs often prioritize health equity. On 26-27 April, 2023, Tufts University’s Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy and Food & Nutrition Innovation Institute held a 2-day National Food is Medicine Summit with leaders, practitioners, and individuals with diverse lived experiences in health care, research, government, advocacy, philanthropy, and the private sector to identify challenges and opportunities to sustainably incorporate FIM services into the health care system and at scale. This report of a meeting describes key themes of the Summit, based on presentations and discussions on momentum around FIM, incorporating FIM in health care, tradeoffs and unintended consequences of various FIM models, scaling of programs, financing and payment mechanisms, educating and engaging the health care workforce, and federal and state government actions and opportunities on FIM. Speakers highlighted examples of recent public and private sector actions on FIM and innovative cross-sector partnerships, including state Medicaid waivers, academic and philanthropic research initiatives, health care system screenings and interventions, and collaborations including community-based organizations and/or entities outside of the food and health care sectors. Challenges and opportunities to broader implementation and scaling of FIM programs identified include incorporating FIM into health care business models, educating the health care workforce, and sustainably scaling FIM programs while leveraging the local connections of community-based organizations. This meeting report highlights recent advances, best practices, challenges, and opportunities discussed at the National Summit to inform future actions on FIM.

Authors: Ridberg RA; Maitin-Shepard M; Garfield K; Seligman HK; Schwartz PM; Terranova J; Yaroch AL; Mozaffarian D | December 1, 2024 | PubMed abstract

The weathering hypothesis proposes that marginalized people experience faster biologic aging due to cumulative stress which translates to chronic disease disparities. We assessed telomere length (TL) differences, an aging biomarker, by sexual orientation (bisexual, gay/lesbian, straight) among 102,258 individuals enrolled in the Resource for Genetic Epidemiology Research on Aging Cohort during 2008 through 2011 (mean age of 60.6 years, 58% female, and 7.6% bisexual/gay/lesbian). We used linear models to estimate differences in telomere length, stratified by sex/gender and adjusted for age (at salivary sample) and socio-demographic variables and Kitagawa-Blinder-Oaxaca decomposition to quantify contributions of participant factors on TL differences. Among females, there was no significant difference in age-adjusted telomere length by sexual orientation after adjustment for socio-demographics (ref: straight; bisexual 0.007, 95%CI: -0.03 to 0.04; lesbian: 0.005, 95%CI: -0.02 to 0.03). Among males, only gay (-0.04, 95%CI: -0.06 to -0.02) but not bisexual (-0.02, 95%CI: -0.06 to 0.02) men had significantly shorter age-adjusted telomere length compared to straight men after adjusting for socio-demographic variables. Decomposition analysis identified ever smoking and marital status as significant drivers of the gay-straight disparity. Studies confirming our findings are needed and the implications of shorter telomeres on gay men’s health requires further investigation.

Authors: Rivera AS; Chao CR; Hechter RC | September 11, 2024 | PubMed abstract

Many studies support the notion that polygenic risk scores (PRS) improve risk prediction for coronary heart disease (CHD) beyond conventional risk factors. However, PRS are not yet considered risk-enhancing factor in guidelines. Our objective was to determine the predictive performance of a commercially available PRS (CARDIO inCode-Score®) compared with the Pooled Cohorts Equations (PCE) in a contemporary, multi-ethnic cohort. Participants (n = 63,070; 67 % female; 18 % non-European) without prior CHD were followed from 2007 through 12/31/2022. The association between the PRS and incident CHD was assessed using Cox regression adjusting for genetic ancestry and risk factors. Event rates were estimated by categories of PCE and by low/intermediate/high genetic risk within PCE categories; risk discrimination and net reclassification improvement (NRI) were also assessed. There were 3,289 incident CHD events during 14 years of follow-up. Adjusted hazard ratio (aHR) for incident CHD per 1 SD increase in PRS was 1.18 (95 % CI:1.14-1.22), and the aHR for the upper vs lower quintile of the PRS was 1.66 (95 % CI:1.49-1.86). The association was consistent in both sexes, in European participants compared with all minority groups combined and was strongest in the first 5 years of follow-up. The increase in the C-statistic was 0.004 (0.747 vs. 0.751; p < 0.0001); the NRI was 2.4 (0.9-3.8) for the entire cohort and 9.7 (7.5-12.0) for intermediate PCE risk individuals. After incorporating high genetic risk, a further 10 percent of participants at borderline/intermediate PCE risk would be candidates for statin therapy. Inclusion of polygenic risk improved identification of primary prevention individuals who may benefit from more intensive risk factor modification.

Authors: Iribarren C; Lu M; Elosua R; Gulati M; Wong ND; Blumenthal RS; Nissen S; Rana JS | June 1, 2024 | PubMed abstract

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%-79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.

Authors: Vabistsevits M; Davey Smith G; Richardson TG; Richmond RC; Sieh W; Rothstein JH; Habel LA; Alexeeff SE; Lloyd-Lewis B; Sanderson E | May 13, 2024 | PubMed abstract

Dietary isothiocyanate (ITC) exposure from cruciferous vegetable (CV) intake may improve non-muscle invasive bladder cancer (NMIBC) prognosis. This study aims to investigate whether genetic variations in key ITC-metabolizing/functioning genes modify the associations between dietary ITC exposure and NMIBC prognosis outcomes. In the Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study), a prospective cohort of 1472 incident NMIBC patients, dietary ITC exposure is assessed by self-reported CV intake and measured in plasma ITC-albumin adducts. Using Cox proportional hazards regression models, stratified by single nucleotide polymorphisms (SNPs) in nine key ITC-metabolizing/functioning genes, it is calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression. The rs15561 in N-acetyltransferase 1 (NAT1) is alter the association between CV intake and progression risk. Multiple SNPs in nuclear factor E2-related factor 2 (NRF2) and nuclear factor kappa B (NFκB) are modify the associations between plasma ITC-albumin adduct level and progression risk (pint < 0.05). No significant association is observed with recurrence risk. Overall, >80% study participants are present with at least one protective genotype per gene, showing an average 65% reduction in progression risk with high dietary ITC exposure. Despite that genetic variations in ITC-metabolizing/functioning genes may modify the effect of dietary ITCs on NMIBC prognosis, dietary recommendation of CV consumption may help improve NMIBC survivorship.

Authors: Wang Z; Kwan ML; Haque R; Singh PK; Goniewicz M; Pratt R; Lee VS; Roh JM; Ergas IJ; Cannavale KL; Loo RK; Aaronson DS; Quesenberry CP; Zhang Y; Ambrosone CB; Kushi LH; Tang L | April 1, 2024 | PubMed abstract

Little is known about SARS-CoV-2 infection and COVID-19 severity among a growing population of cancer survivors. We describe the association of infection and related hospitalization by recency of cancer diagnosis in a large U.S. cohort. Participants were sent electronic surveys between April 2020 and January 2021 to collect information on SARS-CoV-2 infection and potential COVID-19-related risk factors. SARS-CoV-2 infections were identified using survey report of a COVID-19-positive test and electronic health record data. Cumulative incidence of SARS-CoV-2 infection was estimated up to 365 days from baseline survey and stratified by recency of cancer diagnosis. Among those with SARS-CoV-2 infection, we used logistic regression to estimate the association between recency of cancer diagnosis and hospitalization within 30 days of infection. Cumulative incidence of SARS-CoV-2 infection at 365 days was 3.3% [95% confidence interval (CI), 3.2%-3.5%] among those without cancer history and ranged from 2.8% (95% CI, 2.3%-3.5%) to 3.7% (95% CI, 2.9%-4.7%) among those with a history of cancer depending on recency. There was no statistically significant difference in odds of hospitalization within 30 days following SARS-CoV-2 infection by cancer diagnosis recency. Our null findings are consistent with other studies on COVID-19 infection risk in cancer survivors, where COVID-19 severity and sequelae were independent of cancer history and were likely associated with factors such as intensive care unit admission, noncancer comorbid conditions, and long-term care residency. This study can inform COVID-19 risk-counseling of cancer survivors and their caregivers as we continue to contend with COVID-19.

Authors: White LL; Burnett-Hartman AN; Ichikawa LE; Goldberg SR; Chubak J; Spencer Feigelson H; Kamineni A | March 1, 2024 | PubMed abstract

Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies worldwide. While several environmental risk factors for cSCC are well established, there is conflicting evidence on cigarette smoking (and its potential causal effect) and cSCC risk. Furthermore, it is unclear if these potential associations represent causal, modifiable risk factors for cSCC development. This study aims to assess the nature of the associations between cigarette smoking traits (smoking initiation, amount smoked, and lifetime smoking exposure) and cSCC risk using two-sample Mendelian randomization analyses. Genetic instruments, based on common genetic variants associated with cigarette smoking traits (P < 5 × 10-8), were derived from published genome-wide association studies (GWASs). For cSCC, we used GWAS summary statistics from the Kaiser Permanente GERA cohort (7701 cSCC cases and 60,167 controls; all non-Hispanic Whites). We found modest evidence that genetically determined lifetime smoking was associated with cSCC (inverse-variance weighted method: OR[95% CI] = 1.47[1.09-1.98]; P = .012), suggesting it may be a causal risk factor for cSCC. We did not detect any evidence of association between genetically determined smoking initiation or amount smoked and cSCC risk. Study findings highlight the importance of smoking prevention and may support risk-stratified cSCC screening strategies based on carcinogen exposure and other genetic and clinical information.

Authors: Lee T; George CD; Jiang C; Asgari MM; Nijsten T; Pardo LM; Choquet H | March 1, 2024 | PubMed abstract

Basal cell carcinoma (BCC) is one of the most common malignancies worldwide, yet its genetic determinants are incompletely defined. We perform a European ancestry genome-wide association (GWA) meta-analysis and a Hispanic/Latino ancestry GWA meta-analysis and meta-analyze both in a multi-ancestry GWAS meta-analysis of BCC, totaling 50,531 BCC cases and 762,234 controls from four cohorts (GERA, Mass-General Brigham Biobank, UK Biobank, and 23andMe research cohort). Here we identify 122 BCC-associated loci, of which 36 were novel, and subsequently fine-mapped these associations. We also identify an association of the well-known pigment gene SLC45A2 as well as associations at RCC2 and CLPTM1L with BCC in Hispanic/Latinos. We examine these BCC loci for association with cutaneous squamous cell carcinoma (cSCC) in 16,407 SCC cases and 762,486 controls of European ancestry, and 33 SNPs show evidence of association. Our study findings provide important insights into the genetic basis of BCC and cSCC susceptibility.

Authors: Choquet H; Jiang C; Yin J; Kim Y; Hoffmann TJ; 23andMe Research Team; Jorgenson E; Asgari MM | January 5, 2024 | PubMed abstract

Cataract is the leading cause of blindness among the elderly worldwide. Twin and family studies support an important role for genetic factors in cataract susceptibility with heritability estimates up to 58%. To date, 55 loci for cataract have been identified by genome-wide association studies (GWAS), however, much work remains to identify the causal genes. Here, we conducted a transcriptome-wide association study (TWAS) of cataract to prioritize causal genes and identify novel ones, and examine the impact of their expression. We performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 54 tissues (including 49 from the Genotype Tissue Expression (GTEx) Project v8) with cataract using FUSION software. Meta-analyzed GWAS summary statistics from 59,944 cataract cases and 478,571 controls, all of European ancestry and from two cohorts (GERA and UK Biobank) were used. We then examined the expression of the novel genes in the lens tissue using the iSyTE database. Across tissue-specific and multi-tissue analyses, we identified 99 genes for which genetically predicted gene expression was associated with cataract after correcting for multiple testing. Of these 99 genes, 20 (AC007773.1, ANKH, ASIP, ATP13A2, CAPZB, CEP95, COQ6, CREB1, CROCC, DDX5, EFEMP1, EIF2S2, ESRRB, GOSR2, HERC4, INSRR, NIPSNAP2, PICALM, SENP3, and SH3YL1) did not overlap with previously reported cataract-associated loci. Tissue-specific analysis identified 202 significant gene-tissue associations for cataract, of which 166 (82.2%), representing 9 unique genes, were attributed to the previously reported 11q13.3 locus. Tissue-enrichment analysis revealed that gastrointestinal tissues represented one of the highest proportions of the Bonferroni-significant gene-tissue associations (21.3%). Moreover, this gastrointestinal tissue type was the only anatomical category significantly enriched in our results, after correcting for the number of tissue donors and imputable genes for each reference panel. Finally, most of the novel cataract genes (e.g., Capzb) were robustly expressed in iSyTE lens data. Our results provide evidence of the utility of imputation-based TWAS approaches to characterize known GWAS risk loci and identify novel candidate genes that may increase our understanding of cataract etiology. Our findings also highlight the fact that expression of genes associated with cataract susceptibility is not necessarily restricted to lens tissue.

Authors: Choquet H; Duot M; Herrera VA; Shrestha SK; Meyers TJ; Hoffmann TJ; Sangani PK; Lachke SA | January 1, 2024 | PubMed abstract

Maternal inflammation can result from immune dysregulation and metabolic perturbations during pregnancy. Whether conditions associated with inflammation during pregnancy increase the likelihood of autism spectrum disorder (ASD) or other neurodevelopmental disorders (DDs) is not well understood. We conducted a case-control study among children born in California from 2011 to 2016 to investigate maternal immune-mediated and cardiometabolic conditions during pregnancy and risk of ASD (n = 311) and DDs (n = 1291) compared with children from the general population (n = 967). Data on maternal conditions and covariates were retrieved from electronic health records. Maternal genetic data were used to assess a causal relationship. Using multivariable logistic regression, we found that mothers with asthma were more likely to deliver infants later diagnosed with ASD (odds ratio [OR] = 1.62, 95% CI: 1.15-2.29) or DDs (OR = 1.30, 95% CI: 1.02-1.64). Maternal obesity was also associated with child ASD (OR = 1.51, 95% CI: 1.07-2.13). Mothers with both asthma and extreme obesity had the greatest odds of delivering an infant later diagnosed with ASD (OR = 16.9, 95% CI: 5.13-55.71). These increased ASD odds were observed among female children only. Polygenic risk scores for obesity, asthma, and their combination showed no association with ASD risk. Mendelian randomization did not support a causal relationship between maternal conditions and ASD. Inflammatory conditions during pregnancy are associated with risk for neurodevelopmental disorders in children. These risks do not seem to be due to shared genetic risk; rather, inflammatory conditions may share nongenetic risk factors with neurodevelopmental disorders. Children whose mothers have both asthma and obesity during pregnancy may benefit from earlier screening and intervention.

Authors: Croen LA; Ames JL; Qian Y; Alexeeff S; Ashwood P; Gunderson EP; Wu YW; Boghossian AS; Yolken R; Van de Water J; Weiss LA | January 1, 2024 | PubMed abstract

Asthma exacerbations reflect disease severity, affect morbidity and mortality, and may lead to declining lung function. Inflammatory endotypes (e.g. T2-high (eosinophilic)) may play a key role in asthma exacerbations. We aimed to assess whether genetic susceptibility underlies asthma exacerbation risk and additionally tested for an interaction between genetic variants and eosinophilia on exacerbation risk. UK Biobank data were used to perform a genome-wide association study of individuals with asthma and at least one exacerbation compared to individuals with asthma and no history of exacerbations. Individuals with asthma were identified using self-reported data, hospitalisation data and general practitioner records. Exacerbations were identified as either asthma-related hospitalisation, general practitioner record of asthma exacerbation or an oral corticosteroid burst prescription. A logistic regression model adjusted for age, sex, smoking status and genetic ancestry via principal components was used to assess the association between genetic variants and asthma exacerbations. We sought replication for suggestive associations (p<5×10-6) in the GERA cohort. In the UK Biobank, we identified 11 604 cases and 37 890 controls. While no variants reached genome-wide significance (p<5×10-8) in the primary analysis, 116 signals were suggestively significant (p<5×10-6). In GERA, two single nucleotide polymorphisms (rs34643691 and rs149721630) replicated (p<0.05), representing signals near the NTRK3 and ABCA13 genes. Our study has identified reproducible associations with asthma exacerbations in the UK Biobank and GERA cohorts. Confirmation of these findings in different asthma subphenotypes in diverse ancestries and functional investigation will be required to understand their mechanisms of action and potentially inform therapeutic development.

Authors: Edris A; Voorhies K; Lutz SM; Iribarren C; Hall I; Wu AC; Tobin M; Fawcett K; Lahousse L | January 1, 2024 | PubMed abstract

HEARTS in the Americas is the regional adaptation of Global Hearts, the World Health Organization initiative for cardiovascular disease (CVD) prevention and control. Its overarching goal is to drive health services to change managerial and clinical practice in primary care settings to improve hypertension control and CVD risk management. This review describes the HEARTS in the Americas initiative. First, the regional epidemiological situation of CVD mortality and population hypertension control trends are summarized; then the rationale for its main intervention components: the primary care-oriented management system and the HEARTS Clinical Pathway are described. Finally, the key factors for accelerating the expansion of HEARTS are examined: medicines, team-based care, and a system for monitoring and evaluation. Thus far, 33 countries in Latin America and the Caribbean have committed to integrating this program across their primary healthcare network by 2025. The increase in hypertension coverage and control in primary health care settings compared with the traditional model is promising and confirms that the interventions under the HEARTS umbrella are feasible and acceptable to communities, patients, providers, decision-makers, and funders. This review highlights some cases of successful implementation. Scaling up effective treatment for hypertension and optimization of CVD risk management is a pragmatic way to accelerate the reduction of CVD mortality while strengthening primary healthcare systems to respond effectively, with quality, and equitably, to the challenge of non-communicable diseases, not only in low-middle income countries but in all communities globally. HEARTS en las Américas es la adaptación regional de la iniciativa mundial HEARTS, de la Organización Mundial de la Salud, para la prevención y el control de las enfermedades cardiovasculares (ECV). Su objetivo general es impulsar el cambio de la práctica clínica y de la gestión en los entornos de atención primaria, por parte de los servicios de salud, a fin de mejorar el control de la hipertensión y reducir el riesgo de ECV. En esta revisión se describe la iniciativa HEARTS en las Américas. En primer lugar, se resume la situación epidemiológica regional en cuanto a la mortalidad por ECV y las tendencias en el control de la hipertensión a nivel poblacional; a continuación, se explica la razón de ser de los principales componentes de la intervención: el sistema de manejo orientado a la atención primaria y la vía clínica de HEARTS. Por último, se examinan los factores clave para acelerar la expansión de HEARTS: los medicamentos, la atención basada en el trabajo en equipo y un sistema de monitoreo y evaluación. Hasta el momento, 33 países y territorios de América Latina y el Caribe se han comprometido a integrar este programa en toda su red de atención primaria de salud para el 2025. El aumento de la cobertura y del control de la hipertensión en los entornos de atención primaria de salud (en comparación con el modelo tradicional) es prometedor y confirma que las intervenciones que se promueven como parte de HEARTS son factibles y resultan aceptables para las comunidades, los pacientes, los prestadores de servicios de salud, los responsables de la toma de decisiones y los financiadores. En esta revisión se destacan algunos casos de implementación satisfactoria. Ampliar el uso de un tratamiento eficaz de la hipertensión y optimizar el control del riesgo de ECV es una forma pragmática de acelerar la reducción de la mortalidad por ECV y, al mismo tiempo, de fortalecer los sistemas de atención primaria de salud para responder con calidad y de manera eficaz y equitativa al desafío que entrañan las enfermedades no transmisibles, no solo en los países de ingresos bajos o medianos, sino en todas las comunidades a nivel mundial. HEARTS nas Américas é uma adaptação regional da iniciativa mundial HEARTS, da Organização Mundial da Saúde, voltada para prevenção e controle das doenças cardiovasculares (DCV) na Região das Américas. Seu objetivo geral é promover mudanças na prática clínica e na gestão da atenção primária pelos serviços de saúde a fim de melhorar o controle da hipertensão arterial e reduzir o risco de DCV. Esta revisão descreve a iniciativa HEARTS nas Américas. Primeiro, é apresentado um resumo da situação epidemiológica regional relativa à mortalidade por DCV e das tendências no controle da hipertensão arterial em nível populacional. Em seguida, são explicados os motivos por trás dos principais componentes da intervenção: o sistema de manejo focado na atenção primária e o componente clínico da HEARTS. Por fim, são examinados os principais fatores para acelerar a ampliação da HEARTS: medicamentos, atenção baseada no trabalho em equipe e um sistema de monitoramento e avaliação. Até o momento, 33 países e territórios da América Latina e do Caribe se comprometeram a integrar esse programa em toda sua rede de atenção primária à saúde até 2025. Comparado com o modelo tradicional, o aumento da cobertura e do controle da hipertensão arterial nos ambientes de atenção primária à saúde é promissor e confirma que as intervenções promovidas pela HEARTS são exequíveis e aceitas por comunidades, pacientes, prestadores de serviços de saúde, tomadores de decisão e financiadores. Nesta revisão, destacamos alguns casos nos quais a implementação foi satisfatória. Ampliar a aplicação de um tratamento eficaz contra a hipertensão arterial e otimizar o controle do risco de DCV são medidas pragmáticas para acelerar a redução da mortalidade por DCV e, ao mesmo tempo, fortalecer os sistemas de atenção primária à saúde para responder com qualidade, eficácia e equidade ao desafio apresentado pelas doenças não transmissíveis, não apenas nos países de baixa ou média renda, mas no mundo todo.

Authors: Ordunez P; Campbell NRC; DiPette DJ; Jaffe MG; Rosende A; Martínez R; Gamarra A; Lombardi C; Parra N; Rodríguez L; Rodríguez Y; Brettler J | January 1, 2024 | PubMed abstract

Asthma and chronic obstructive pulmonary disease (COPD) have distinct and overlapping genetic and clinical features. We sought to test the hypothesis that polygenic risk scores (PRSs) for asthma (PRSAsthma) and spirometry (FEV1 and FEV1/forced vital capacity; PRSspiro) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO). We developed and tested 2 asthma PRSs and applied the higher performing PRSAsthma and a previously published PRSspiro to research (Genetic Epidemiology of COPD study and Childhood Asthma Management Program, with spirometry) and electronic health record-based (Mass General Brigham Biobank and Genetic Epidemiology Research on Adult Health and Aging [GERA]) studies. We assessed the association of PRSs with COPD and asthma using modified random-effects and binary-effects meta-analyses, and ACO and asthma exacerbations in specific cohorts. Models were adjusted for confounders and genetic ancestry. In meta-analyses of 102,477 participants, the PRSAsthma (odds ratio [OR] per SD, 1.16 [95% CI, 1.14-1.19]) and PRSspiro (OR per SD, 1.19 [95% CI, 1.17-1.22]) both predicted asthma, whereas the PRSspiro predicted COPD (OR per SD, 1.25 [95% CI, 1.21-1.30]). However, results differed by cohort. The PRSspiro was not associated with COPD in GERA and Mass General Brigham Biobank. In the Genetic Epidemiology of COPD study, the PRSAsthma (OR per SD: Whites, 1.3; African Americans, 1.2) and PRSspiro (OR per SD: Whites, 2.2; African Americans, 1.6) were both associated with ACO. In GERA, the PRSAsthma was associated with asthma exacerbations (OR, 1.18) in Whites; the PRSspiro was associated with asthma exacerbations in White, LatinX, and East Asian participants. PRSs for asthma and spirometry are both associated with ACO and asthma exacerbations. Genetic prediction performance differs in research versus electronic health record-based cohorts.

Authors: Moll M; Sordillo JE; Ghosh AJ; Hayden LP; McDermott G; McGeachie MJ; Dahlin A; Tiwari A; Manmadkar MG; Abston ED; Pavuluri C; Saferali A; Begum S; Ziniti JP; Gulsvik A; Bakke PS; Aschard H; Iribarren C; Hersh CP; Sparks JA; Hobbs BD; Lasky-Su JA; Silverman EK; Weiss ST; Wu AC; Cho MH | December 1, 2023 | PubMed abstract

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Authors: Thomas M; Su YR; Rosenthal EA; Sakoda LC; Schmit SL; Timofeeva MN; Chen Z; Fernandez-Rozadilla C; Law PJ; Murphy N; Carreras-Torres R; Diez-Obrero V; van Duijnhoven FJB; Jiang S; Shin A; Wolk A; Phipps AI; Burnett-Hartman A; Gsur A; Chan AT; Zauber AG; Wu AH; Lindblom A; Um CY; Tangen CM; Gignoux C; Newton C; Haiman CA; Qu C; Bishop DT; Buchanan DD; Crosslin DR; Conti DV; Kim DH; Hauser E; White E; Siegel E; Schumacher FR; Rennert G; Giles GG; Hampel H; Brenner H; Oze I; Oh JH; Lee JK; Schneider JL; Chang-Claude J; Kim J; Huyghe JR; Zheng J; Hampe J; Greenson J; Hopper JL; Palmer JR; Visvanathan K; Matsuo K; Matsuda K; Jung KJ; Li L; Le Marchand L; Vodickova L; Bujanda L; Gunter MJ; Matejcic M; Jenkins MA; Slattery ML; D'Amato M; Wang M; Hoffmeister M; Woods MO; Kim M; Song M; Iwasaki M; Du M; Udaltsova N; Sawada N; Vodicka P; Campbell PT; Newcomb PA; Cai Q; Pearlman R; Pai RK; Schoen RE; Steinfelder RS; Haile RW; Vandenputtelaar R; Prentice RL; Küry S; Castellví-Bel S; Tsugane S; Berndt SI; Lee SC; Brezina S; Weinstein SJ; Chanock SJ; Jee SH; Kweon SS; Vadaparampil S; Harrison TA; Yamaji T; Keku TO; Vymetalkova V; Arndt V; Jia WH; Shu XO; Lin Y; Ahn YO; Stadler ZK; Van Guelpen B; Ulrich CM; Platz EA; Potter JD; Li CI; Meester R; Moreno V; Figueiredo JC; Casey G; Lansdorp Vogelaar I; Dunlop MG; Gruber SB; Hayes RB; Pharoah PDP; Houlston RS; Jarvik GP; Tomlinson IP; Zheng W; Corley DA; Peters U; Hsu L | October 2, 2023 | PubMed abstract

Observational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR). We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects. Next, we examined the effect of MD on breast cancer risk, including risk of molecular subtypes, and accounting for genetic pleiotropy. Finally, we used MVMR to evaluate whether the protective effect of childhood adiposity on breast cancer was mediated by MD. Childhood adiposity had a strong inverse effect on mammographic DA, while adulthood adiposity increased NDA. Later menarche had an effect of increasing DA and PD, but when accounting for childhood adiposity, this effect attenuated to the null. DA and PD had a risk-increasing effect on breast cancer across all subtypes. The MD single-nucleotide polymorphism (SNP) estimates were extremely heterogeneous, and examination of the SNPs suggested different mechanisms may be linking MD and breast cancer. Finally, MR mediation analysis estimated that 56% (95% CIs [32% – 79%]) of the childhood adiposity effect on breast cancer risk was mediated via DA. In this work, we sought to disentangle the relationship between factors affecting MD and breast cancer. We showed that higher childhood adiposity decreases mammographic DA, which subsequently leads to reduced breast cancer risk. Understanding this mechanism is of great importance for identifying potential targets of intervention, since advocating weight gain in childhood would not be recommended.

Authors: Vabistsevits M; Smith GD; Richardson TG; Richmond RC; Sieh W; Rothstein JH; Habel LA; Alexeeff SE; Lloyd-Lewis B; Sanderson E | September 2, 2023 | PubMed abstract

Lung cancer screening (LCS) guidelines in the United States recommend LCS for those age 50-80 years with at least 20 pack-years smoking history who currently smoke or quit within the last 15 years. We tested the performance of simple smoking-related criteria derived from electronic health record (EHR) data and developed and tested the performance of a multivariable model in predicting LCS eligibility. Analyses were completed within the Population-based Research to Optimize the Screening Process Lung Consortium (PROSPR-Lung). In our primary validity analyses, the reference standard LCS eligibility was based on self-reported smoking data collected via survey. Within one PROSPR-Lung health system, we used a training data set and penalized multivariable logistic regression using the Least Absolute Shrinkage and Selection Operator to select EHR-based variables into the prediction model including demographics, smoking history, diagnoses, and prescription medications. A separate test data set assessed model performance. We also conducted external validation analysis in a separate health system and reported AUC, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy metrics associated with the Youden Index. There were 14,214 individuals with survey data to assess LCS eligibility in primary analyses. The overall performance for assigning LCS eligibility status as measured by the AUC values at the two health systems was 0.940 and 0.938. At the Youden Index cutoff value, performance metrics were as follows: accuracy, 0.855 and 0.895; sensitivity, 0.886 and 0.920; specificity, 0.896 and 0.850; PPV, 0.357 and 0.444; and NPV, 0.988 and 0.992. Our results suggest that health systems can use an EHR-derived multivariable prediction model to aid in the identification of those who may be eligible for LCS.

Authors: Burnett-Hartman AN; Powers JD; Hixon BP; Carroll NM; Frankland TB; Honda SA; Saia C; Rendle KA; Greenlee RT; Neslund-Dudas C; Zheng Y; Vachani A; Ritzwoller DP | September 1, 2023 | PubMed abstract

Genome-wide association studies (GWASs) have identified more than 130 genetic susceptibility loci for migraine; however, how most of these loci impact migraine development is unknown. To identify novel genes associated with migraine and interpret the transcriptional products of those genes, we conducted a transcriptome-wide association study (TWAS). We performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 53 tissues and migraine susceptibility using FUSION software. Meta-analyzed GWAS summary statistics from 26,052 migraine cases and 487,214 controls, all of European ancestry and from two cohorts (the Kaiser Permanente GERA and the UK Biobank), were used. We evaluated the associations for genes after conditioning on variant-level effects from GWAS, and we tested for colocalization of GWAS migraine-associated loci and expression quantitative trait loci (eQTLs). Across tissue-specific and multi-tissue analyses, we identified 53 genes for which genetically predicted gene expression was associated with migraine after correcting for multiple testing. Of these 53 genes, 10 (ATF5, CNTNAP1, KTN1-AS1, NEIL1, NEK4, NNT, PNKP, RUFY2, TUBG2, and VAT1) did not overlap known migraine-associated loci identified from GWAS. Tissue-specific analysis identified 45 gene-tissue pairs and cardiovascular tissues represented the highest proportion of the Bonferroni-significant gene-tissue pairs (n = 22 [49%]), followed by brain tissues (n = 6 [13%]), and gastrointestinal tissues (n = 4 [9%]). Colocalization analyses provided evidence of shared genetic variants underlying eQTL and GWAS signals in 18 of the gene-tissue pairs (40%). Our TWAS reports novel genes for migraine and highlights the important contribution of brain, cardiovascular, and gastrointestinal tissues in migraine susceptibility.

Authors: Meyers TJ; Yin J; Herrera VA; Pressman AR; Hoffmann TJ; Schaefer C; Avins AL; Choquet H | July 13, 2023 | PubMed abstract

To investigate the association of genetically determined primary open-angle glaucoma (POAG), myopic refractive error (RE), type 2 diabetes (T2D), blood pressure (BP), body mass index (BMI), cigarette smoking, and alcohol consumption with the risk of age-related cataract. To assess potential causal effects of clinical or behavioral factors on cataract risk, we conducted two-sample Mendelian randomization analyses. Genetic instruments, based on common genetic variants associated with risk factors at genome-wide significance (P < 5 × 10-8), were derived from published genome-wide association studies (GWAS). For age-related cataract, we used GWAS summary statistics from our previous GWAS conducted in the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (28,092 cataract cases and 50,487 controls; all non-Hispanic whites) or in the UK Biobank (31,852 cataract cases and 428,084 controls; all European-descent individuals). We used the inverse-variance weighted (IVW) method as our primary source of Mendelian randomization estimates and conducted common sensitivity analyses. We found that genetically determined POAG and mean spherical equivalent RE were significantly associated with cataract risk (IVW model: odds ratio [OR] = 1.04; 95% confidence interval [CI], 1.01-1.08; P = 0.018; per diopter more hyperopic: OR = 0.92; 95% CI, 0.89-0.93; P = 6.51 × 10-13, respectively). In contrast, genetically determined T2D, BP, BMI, cigarette smoking, or alcohol consumption were not associated with cataract risk (P > 0.05). Our results provide evidence that genetic risks for POAG and myopia may be causal risk factors for age-related cataract. These results are consistent with previous observational studies reporting associations of myopia with cataract risk. This information may support population cataract risk stratification and screening strategies.

Authors: Jiang C; Melles RB; Sangani P; Hoffmann TJ; Hysi PG; Glymour MM; Jorgenson E; Lachke SA; Choquet H | July 3, 2023 | PubMed abstract

High recurrence and progression rates are major clinical challenges for non-muscle-invasive bladder cancer (NMIBC). Dietary isothiocyanates (ITCs), phytochemicals primarily from cruciferous vegetables (CV), show strong anticancer activities in preclinical BC models, yet their effect on NMIBC prognosis remains unknown. This study aimed to investigate the associations of dietary ITC exposure at diagnosis with NMIBC recurrence and progression. The study analyzed 1143 participants from the Be-Well study, a prospective cohort of newly diagnosed NMIBC cases in 2015-2019 with no prior history of BC. Dietary ITC exposure was indicated by self-reported CV intake, estimated ITC intake, urinary metabolites, and plasma ITC-albumin adducts. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression, and unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for delayed and multiple recurrence. Over a mean follow-up of 25 mo, 347 (30%) developed recurrence and 77 (6.7%) had disease progression. Despite no significant associations with the overall risk of recurrence, urinary ITC metabolites (OR: 1.96; 95% CI: 1.01, 4.43) and dietary ITC intake (OR: 2.13; 95% CI: 1.03, 4.50) were associated with late recurrence after 12-mo postdiagnosis compared with before 12-mo postdiagnosis. Raw CV intake was associated with reduced odds of having ≥2 recurrences compared with having one (OR: 0.34; 95% CI: 0.16, 0.68). Higher plasma concentrations of ITC-albumin adducts were associated with a reduced risk of progression, including progression to muscle-invasive disease (for benzyl ITC, HR: 0.40; 95% CI: 0.17, 0.93; for phenethyl ITC, HR: 0.40; 95% CI: 0.19, 0.86). Our findings indicate the possible beneficial role of dietary ITCs in NMIBC prognosis. Given the compelling preclinical evidence, increasing dietary ITC exposure with CV intake could be a promising strategy to attenuate recurrence and progression risks in patients with NMIBC.

Authors: Wang Z; Kwan ML; Haque R; Goniewicz M; Pratt R; Lee VS; Roh JM; Ergas IJ; Cannavale KL; Loo RK; Aaronson DS; Quesenberry CP; Zhang Y; Ambrosone CB; Kushi LH; Tang L | June 1, 2023 | PubMed abstract

Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults. A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases. In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10-5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1, CRADD and DST for the OCS burst outcome and GM2A, SNW1, CACNA1C, DPH1, and RPS10 for the asthma-related exacerbation outcome. Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4.

Authors: Wang AL; Lahousse L; Dahlin A; Edris A; McGeachie M; Lutz SM; Sordillo JE; Brusselle G; Lasky-Su J; Weiss ST; Iribarren C; Lu MX; Tantisira KG; Wu AC | May 1, 2023 | PubMed abstract

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Authors: Mathieson I; Day FR; Barban N; Tropf FC; Brazel DM; eQTLGen Consortium; BIOS Consortium; Vaez A; van Zuydam N; Bitarello BD; Gardner EJ; Akimova ET; Azad A; Bergmann S; Bielak LF; Boomsma DI; Bosak K; Brumat M; Buring JE; Cesarini D; Chasman DI; Chavarro JE; Cocca M; Concas MP; Davey Smith G; Davies G; Deary IJ; Esko T; Faul JD; FinnGen Study; Franco O; Ganna A; Gaskins AJ; Gelemanovic A; de Geus EJC; Gieger C; Girotto G; Gopinath B; Grabe HJ; Gunderson EP; Hayward C; He C; van Heemst D; Hill WD; Hoffmann ER; Homuth G; Hottenga JJ; Huang H; Hyppӧnen E; Ikram MA; Jansen R; Johannesson M; Kamali Z; Kardia SLR; Kavousi M; Kifley A; Kiiskinen T; Kraft P; Kühnel B; Langenberg C; Liew G; Lifelines Cohort Study; Lind PA; Luan J; Mägi R; Magnusson PKE; Mahajan A; Martin NG; Mbarek H; McCarthy MI; McMahon G; Medland SE; Meitinger T; Metspalu A; Mihailov E; Milani L; Missmer SA; Mitchell P; Møllegaard S; Mook-Kanamori DO; Morgan A; van der Most PJ; de Mutsert R; Nauck M; Nolte IM; Noordam R; Penninx BWJH; Peters A; Peyser PA; Polašek O; Power C; Pribisalic A; Redmond P; Rich-Edwards JW; Ridker PM; Rietveld CA; Ring SM; Rose LM; Rueedi R; Shukla V; Smith JA; Stankovic S; Stefánsson K; Stöckl D; Strauch K; Swertz MA; Teumer A; Thorleifsson G; Thorsteinsdottir U; Thurik AR; Timpson NJ; Turman C; Uitterlinden AG; Waldenberger M; Wareham NJ; Weir DR; Willemsen G; Zhao JH; Zhao W; Zhao Y; Snieder H; den Hoed M; Ong KK; Mills MC; Perry JRB | May 1, 2023 | PubMed abstract

The coronavirus disease (COVID-19) pandemic and its economic consequences may disproportionately impact cancer survivors and their overall health-related quality of life. The objective of this study was to examine whether cancer survivors experienced higher levels of financial strain or food insecurity compared to those without a history of cancer. Kaiser Permanente Research Bank (KPRB) study participants were invited to complete a series of electronic surveys starting April 2020 to assess the impact of the COVID-19 pandemic. Participants who completed the initial survey and one follow-up survey were included. The odds of financial strain and food insecurity in those with and without a history of cancer were estimated using multinomial logistic regression. Cancer survivors (n = 16,231) had lower odds of reporting “somewhat hard” (AOR = 0.77) and “very hard” (AOR = 0.67) financial strain, and food insecurity “sometimes” (AOR = 0.70) and “often” (AOR = 0.55) compared to those with no history of cancer (n = 88,409). Non-Hispanic (NH) Black and Hispanic cancer survivors had higher odds compared to NH Whites of reporting financial strain and food insecurity. Smokers and those with multiple comorbidities had higher odds of reporting financial strain and food insecurity among cancer survivors. While cancer survivors overall did not report greater financial strain or food insecurity than individuals without a history of cancer, subsets of cancer survivors are experiencing greater social risks during the pandemic and should be prioritized for screening for social risk factors. Incorporating screening for social risk factors into care coordination workflows for subsets of cancer survivors should be a priority.

Authors: Kelly C; White LL; Scott SG; Feigelson HS; Burnett-Hartman AN | April 1, 2023 | PubMed abstract

Authors: Kim Y; Yin J; Le Breton S; Jorgenson E; Huang H; Choquet H; Asgari MM | April 1, 2023 | PubMed abstract

Polygenic risk scores (PRS) which summarize individuals’ genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. The proposed model has potential utility in risk-stratified colorectal cancer prevention.

Authors: Su YR; Sakoda LC; Jeon J; Thomas M; Lin Y; Schneider JL; Udaltsova N; Lee JK; Lansdorp-Vogelaar I; Peterse EFP; Zauber AG; Zheng J; Zheng Y; Hauser E; Baron JA; Barry EL; Bishop DT; Brenner H; Buchanan DD; Burnett-Hartman A; Campbell PT; Casey G; Castellví-Bel S; Chan AT; Chang-Claude J; Figueiredo JC; Gallinger SJ; Giles GG; Gruber SB; Gsur A; Gunter MJ; Hampe J; Hampel H; Harrison TA; Hoffmeister M; Hua X; Huyghe JR; Jenkins MA; Keku TO; Marchand LL; Li L; Lindblom A; Moreno V; Newcomb PA; Pharoah PDP; Platz EA; Potter JD; Qu C; Rennert G; Schoen RE; Slattery ML; Song M; van Duijnhoven FJB; Van Guelpen B; Vodicka P; Wolk A; Woods MO; Wu AH; Hayes RB; Peters U; Corley DA; Hsu L | March 6, 2023 | PubMed abstract

Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress. We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships. We included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS. We observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of β=-0.15 [95% confidence interval (CI): -0.27, -0.03], β=-0.14 (95% CI: -0.28, -0.002), β=-0.22 (95% CI: -0.23, -0.10), β=-0.06 (95% CI: -0.18, 0.06), and β=-0.25 (95% CI: -0.37, -0.14), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: ORPFNA=0.56 (95% CI: 0.38, 0.83), ORPFDA=0.52 (95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [-0.28; 95% highest posterior density (HPD): -0.44, -0.14] and decreased odds of large-for-gestational-age (OR=0.49; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress. Our large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans. https://doi.org/10.1289/EHP10723.

Authors: Padula AM; Ning X; Bakre S; Barrett ES; Bastain T; Bennett DH; Bloom MS; Breton CV; Dunlop AL; Eick SM; Ferrara A; Fleisch A; Geiger S; Goin DE; Kannan K; Karagas MR; Korrick S; Meeker JD; Morello-Frosch R; O'Connor TG; Oken E; Robinson M; Romano ME; Schantz SL; Schmidt RJ; Starling AP; Zhu Y; Hamra GB; Woodruff TJ; program collaborators for Environmental influences on Child Health Outcomes | March 1, 2023 | PubMed abstract

Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the CNS. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n = 41 505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two independent datasets, UK Biobank [area under the curve (AUC) = 0.73, 95% confidence interval (CI): 0.72-0.74, P = 6.41 × 10-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5 × 10-53). Individuals within the top 10% of PRS were at higher than 5-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8 × 10-45) and 15-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7 × 10-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS in clinical risk models increased the risk discrimination by 13% to 26% over models based only on conventional risk factors in UK Biobank and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signalling cascades, nominated promising genetic candidate programmes for functional characterization. These pathways include inflammatory signalling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multicase families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P < 0.001), consistent with a partial overlap between the genetics of susceptibility and end-organ tissue injury. Mendelian randomization analysis suggested an effect of multiple sclerosis susceptibility on thalamic volume, which was further indicated to be through horizontal pleiotropy rather than a causal effect. In summary, this study indicates important, replicable associations of PRS with enhanced risk assessment and radiographic outcomes of tissue injury, potentially informing targeted screening and prevention strategies.

Authors: Shams H; Shao X; Santaniello A; Kirkish G; Harroud A; Ma Q; Isobe N; University of California San Francisco MS-EPIC Team; Schaefer CA; McCauley JL; Cree BAC; Didonna A; Baranzini SE; Patsopoulos NA; Hauser SL; Barcellos LF; Henry RG; Oksenberg JR | February 13, 2023 | PubMed abstract

Sleep in childhood is affected by behavioral, environmental, and parental factors. We propose that these factors were altered during the COVID-19 pandemic. This study investigates sleep habit changes during the pandemic in 528 children 4-12 years old in the US, leveraging data from the Environmental Influences on Child Health Outcomes (ECHO) Program. Data collection occurred in July 2019-March 2020 (pre-pandemic) and two pandemic periods: December 2020-April 2021 and May-August 2021. Qualitative interviews were performed in 38 participants. We found no changes in sleep duration, but a shift to later sleep midpoint during the pandemic periods. There was an increase in latency at the first pandemic collection period but no increase in the frequency of bedtime resistance, and a reduced frequency of naps during the pandemic. Qualitative interviews revealed that parents prioritized routines to maintain sleep duration but were more flexible regarding timing. Children from racial/ethnic minoritized communities slept less at night, had later sleep midpoint, and napped more frequently across all collection periods, warranting in-depth investigation to examine and address root causes. The COVID-19 pandemic significantly impacted children sleep, but parental knowledge of the importance of sleep might have played a significant protective role. During the COVID-19 pandemic, US children changed their sleep habits, going to bed and waking up later, but their sleep duration did not change. Sleep latency was longer. Parental knowledge of sleep importance might have played a protective role. Regardless of data collection periods, children from racial/ethnic minoritized communities slept less and went to bed later. This is one of the first study on this topic in the US, including prospective pre-pandemic qualitative and quantitative data on sleep habits. Our findings highlight the pandemic long-term impact on childhood sleep. Results warrants further investigations on implications for overall childhood health.

Authors: Lucchini M; Bekelman TA; Li M; Knapp EA; Dong Y; Ballard S; Deoni S; Dunlop AL; Elliott AJ; Ferrara A; Friedman C; Galarce M; Gilbert-Diamond D; Glueck D; Hedderson M; Hockett CW; Karagas MR; LeBourgeois MK; Margolis A; McDonald J; Ngai P; Pellerite M; Sauder K; Ma T; Dabelea D; Environmental influences on Child Health Outcomes | February 1, 2023 | PubMed abstract

Background: Opioid use has disproportionally impacted pregnant people and their fetuses. Previous studies describing opioid use among pregnant people are limited by geographic location, type of medical coverage, and small sample size. We described characteristics of a large, diverse group of pregnant people who were enrolled in the Environmental Influences on Child Health Outcomes (ECHO) Program, and determined which characteristics were associated with opioid use during pregnancy. Materials and Methods: Cross-sectional data obtained from 21,905 pregnancies of individuals across the United States enrolled in the ECHO between 1990 and 2021 were analyzed. Medical records, laboratory testing, and self-report were used to determine opioid-exposed pregnancies. Multiple imputation methods using fully conditional specification with a discriminant function accounted for missing characteristics data. Results: Opioid use was present in 2.8% (n = 591) of pregnancies. The majority of people who used opioids in pregnancy were non-Hispanic White (67%) and had at least some college education (69%). Those who used opioids reported high rates of alcohol use (32%) and tobacco use (39%) during the pregnancy; although data were incomplete, only 5% reported heroin use and 86% of opioid use originated from a prescription. After adjustment, non-Hispanic White race, pregnancy during the years 2010-2012, higher parity, tobacco use, and use of illegal drugs during pregnancy were each significantly associated with opioid use during pregnancy. In addition, maternal depression was associated with increased odds of opioid use during pregnancy by more than two-fold (adjusted odds ratio 2.42, 95% confidence interval: 1.95-3.01). Conclusions: In this large study of pregnancies from across the United States, we found several factors that were associated with opioid use among pregnant people. Further studies examining screening for depression and polysubstance use may be useful for targeted interventions to prevent detrimental opioid use during pregnancy, while further elucidation of the reasons for use of prescription opioids during pregnancy should be further explored.

Authors: Nguyen, Ruby H. N.; Knapp, Emily A.; Li, Xiuhong; Camargo, Carlos A.; Conradt, Elisabeth; Cowell, Whitney; Derefinko, Karen J.; Elliott, Amy J.; Friedman, Alexander M.; Khurana Hershey, Gurjit K.; Hofheimer, Julie A.; Lester, Barry M.; McEvoy, Cindy T.; Neiderhiser, Jenae M.; Oken, Emily; Ondersma, Steven J.; Sathyanarayana, Sheela; Stabler, Meagan E.; Stroustrup, Annemarie; Tung, Irene; McGrath, Monica | February 1, 2023 | PubMed abstract

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values<0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Authors: Thomas M; Su YR; Rosenthal EA; Sakoda LC; Schmit SL; Timofeeva MN; Chen Z; Fernandez-Rozadilla C; Law PJ; Murphy N; Carreras-Torres R; Diez-Obrero V; van Duijnhoven FJ; Jiang S; Shin A; Wolk A; Phipps AI; Burnett-Hartman A; Gsur A; Chan AT; Zauber AG; Wu AH; Lindblom A; Um CY; Tangen CM; Gignoux C; Newton C; Haiman CA; Qu C; Bishop DT; Buchanan DD; Crosslin DR; Conti DV; Kim DH; Hauser E; White E; Siegel E; Schumacher FR; Rennert G; Giles GG; Hampel H; Brenner H; Oze I; Oh JH; Lee JK; Schneider JL; Chang-Claude J; Kim J; Huyghe JR; Zheng J; Hampe J; Greenson J; Hopper JL; Palmer JR; Visvanathan K; Matsuo K; Matsuda K; Jung KJ; Li L; Marchand LL; Vodickova L; Bujanda L; Gunter MJ; Matejcic M; Jenkins MA; Slattery ML; D'Amato M; Wang M; Hoffmeister M; Woods MO; Kim M; Song M; Iwasaki M; Du M; Udaltsova N; Sawada N; Vodicka P; Campbell PT; Newcomb PA; Cai Q; Pearlman R; Pai RK; Schoen RE; Steinfelder RS; Haile RW; Vandenputtelaar R; Prentice RL; Küry S; Castellví-Bel S; Tsugane S; Berndt SI; Lee SC; Brezina S; Weinstein SJ; Chanock SJ; Jee SH; Kweon SS; Vadaparampil S; Harrison TA; Yamaji T; Keku TO; Vymetalkova V; Arndt V; Jia WH; Shu XO; Lin Y; Ahn YO; Stadler ZK; Van Guelpen B; Ulrich CM; Platz EA; Potter JD; Li CI; Meester R; Moreno V; Figueiredo JC; Casey G; Vogelaar IL; Dunlop MG; Gruber SB; Hayes RB; Pharoah PDP; Houlston RS; Jarvik GP; Tomlinson IP; Zheng W; Corley DA; Peters U; Hsu L | January 19, 2023 | PubMed abstract

Some evidence suggests that neighborhood socioeconomic disadvantage is associated with dementia-related outcomes. However, prior research is predominantly among non-Latino Whites. We evaluated the association between neighborhood disadvantage (Area Deprivation Index [ADI]) and dementia incidence in Asian American (n = 18,103) and non-Latino White (n = 149,385) members of a Northern California integrated health care delivery system aged 60 to 89 at baseline. Race/ethnicity-specific Cox proportional hazards models adjusted for individual-level age, sex, socioeconomic measures, and block group population density estimated hazard ratios (HRs) for dementia. Among non-Latino Whites, ADI was associated with dementia incidence (most vs. least disadvantaged ADI quintile HR = 1.09, 95% confidence interval [CI] = 1.02-1.15). Among Asian Americans, associations were close to null (e.g., most vs. least disadvantaged ADI quintile HR = 1.01, 95% CI = 0.85-1.21). ADI was associated with dementia incidence among non-Latino Whites but not Asian Americans. Understanding the potentially different mechanisms driving dementia incidence in these groups could inform dementia prevention efforts.

Authors: Mobley TM; Shaw C; Hayes-Larson E; Fong J; Gilsanz P; Gee GC; Brookmeyer R; Whitmer RA; Casey JA; Mayeda ER | January 1, 2023 | PubMed abstract

Our primary purpose is to understand comorbidities and health outcomes associated with electronic nicotine delivery systems (ENDS) use. Study participants were Kaiser Permanente (KP) members from eight US regions who joined the Kaiser Permanente Research Bank (KPRB) from September 2015 through December 2019 and completed a questionnaire assessing demographic and behavioral factors, including ENDS and traditional cigarette use. Medical history and health outcomes were obtained from electronic health records. We used multinomial logistic regression to estimate odd ratios (ORs) and 95% confidence intervals (CIs) of current and former ENDS use according to member characteristics, behavioral factors, and clinical history. We used Cox regression to estimate hazard ratios (HRs) and 95% CIs comparing risk of health outcomes according to ENDS use. Of 119 593 participants, 1594 (1%) reported current ENDS use and 5603 (5%) reported past ENDS use. ENDS users were more likely to be younger, male, gay or lesbian, and American Indian / Alaskan Native or Asian. After adjustment for confounding, current ENDS use was associated with current traditional cigarette use (OR = 39.55; CI:33.44-46.77), current marijuana use (OR = 6.72; CI:5.61-8.05), history of lung cancer (OR = 2.64; CI:1.42-4.92), non-stroke cerebral vascular disease (OR = 1.55; CI:1.21-1.99), and chronic obstructive pulmonary disease (OR = 2.16; CI:1.77-2.63). Current ENDS use was also associated with increased risk of emergency room (ER) visits (HR = 1.17; CI: 1.05-1.30) and death (HR = 1.84; CI:1.02-3.32). Concurrent traditional cigarette use, marijuana use, and comorbidities were prevalent among those who used ENDS, and current ENDS use was associated with an increased risk of ER visits and death. Additional research focused on health risks associated with concurrent ENDS and traditional cigarette use in those with underlying comorbidities is needed.

Authors: Goldberg Scott S; Feigelson HS; Powers JD; Clennin MN; Lyons JA; Gray MT; Vachani A; Burnett-Hartman AN | January 1, 2023 | PubMed abstract

Introduction: Long axial length (AL) is a risk factor for myopia. Although family studies indicate that AL has an important genetic component with heritability estimates up to 0.94, there have been few reports of AL-associated loci. Methods: Here, we conducted a multiethnic genome-wide association study (GWAS) of AL in 19,420 adults of European, Latino, Asian, and African ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, with replication in a subset of the Consortium for Refractive Error and Myopia (CREAM) cohorts of European or Asian ancestry. We further examined the effect of the identified loci on the mean spherical equivalent (MSE) within the GERA cohort. We also performed genome-wide genetic correlation analyses to quantify the genetic overlap between AL and MSE or myopia risk in the GERA European ancestry sample. Results: Our multiethnic GWA analysis of AL identified a total of 16 genomic loci, of which 5 are novel. We found that all AL-associated loci were significantly associated with MSE after Bonferroni correction. We also found that AL was genetically correlated with MSE (rg = -0.83; SE, 0.04; p = 1.95 × 10-89) and myopia (rg = 0.80; SE, 0.05; p = 2.84 × 10-55). Finally, we estimated the array heritability for AL in the GERA European ancestry sample using LD score regression, and found an overall heritability estimate of 0.37 (s.e. = 0.04). Discussion: In this large and multiethnic study, we identified novel loci, associated with AL at a genome-wide significance level, increasing substantially our understanding of the etiology of AL variation. Our results also demonstrate an association between AL-associated loci and MSE and a shared genetic basis between AL and myopia risk.

Authors: Jiang C; Melles RB; Yin J; Fan Q; Guo X; Cheng CY; He M; Mackey DA; Guggenheim JA; Klaver C; Consortium for Refractive Error and Myopia (CREAM); Nair KS; Jorgenson E; Choquet H | January 1, 2023 | PubMed abstract

Understanding how sleep, sedentary behavior (SED), and physical activity (PA) (24-h movement profile) changes across pregnancy in individuals with prepregnancy overweight or obesity and how parity (previous births) impacts these changes can help inform interventions. In 155 participants, movement was measured using wrist-worn accelerometers, and sleep was self-reported in early (8-15 wk) and late (29-38 wk) pregnancy. The 24-hour movement profiles were analyzed using compositional analyses. Nulliparous participants (no previous births) spent 33.95%, 38.14%, 25.32%, and 2.58% of the 24-hour day in early pregnancy in sleep, SED, light-intensity PA, and moderate/vigorous-intensity PA, respectively. Multiparous participants (≥1 previous birth) spent 2.50 percentage points less in SED (mean log-ratio difference = -0.068; 95% confidence interval [CI], -0.129 to -0.009) and 2.73 percentage points more in light-intensity PA (mean log-ratio difference = 0.102; 95% CI, 0.035 to 0.180). From early to late pregnancy, participants decreased the proportion of the 24-hour day spent asleep by 1.67 percentage points (mean log-ratio difference = -0.050; 95% CI, -0.092 to -0.011) and increased light-intensity PA by 1.56 percentage points (mean log-ratio difference = 0.057; 95% CI, 0.003 to 0.108), with no change in other behaviors. Nulliparous and multiparous individuals with prepregnancy overweight or obesity both had high levels of SED, with no change across pregnancy, and may require interventions to reduce  SED.

Authors: Badon SE; Ferrara A; Gabriel KP; Avalos LA; Hedderson MM | December 1, 2022 | PubMed abstract

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes1-5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes6, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

Authors: Kessler, Michael D.; Damask, Amy; O'Keeffe, Sean; Banerjee, Nilanjana; Li, Dadong; Watanabe, Kyoko; Marketta, Anthony; Van Meter, Michael; Semrau, Stefan; Horowitz, Julie; Tang, Jing; Kosmicki, Jack A.; Rajagopal, Veera M.; Zou, Yuxin; Houvras, Yariv; Ghosh, Arkopravo; Gillies, Christopher; Mbatchou, Joelle; White, Ryan R.; Verweij, Niek; Bovijn, Jonas; Parikshak, Neelroop N.; LeBlanc, Michelle G.; Jones, Marcus; Regeneron Genetics Center; GHS-RGC DiscovEHR Collaboration; Glass, David J.; Lotta, Luca A.; Cantor, Michael N.; Atwal, Gurinder S.; Locke, Adam E.; Ferreira, Manuel A. R.; Deering, Raquel; Paulding, Charles; Shuldiner, Alan R.; Thurston, Gavin; Ferrando, Adolfo A.; Salerno, Will; Reid, Jeffrey G.; Overton, John D.; Marchini, Jonathan; Kang, Hyun M.; Baras, Aris; Abecasis, Gonçalo R.; Jorgenson, Eric | December 1, 2022 | PubMed abstract

QT interval length is an important risk factor for adverse cardiovascular outcomes; however, the genetic architecture of QT interval remains incompletely understood. We conducted a genome-wide association study of 76,995 ancestrally diverse Kaiser Permanente Northern California members enrolled in the Genetic Epidemiology Research on Adult Health and Aging cohort using 448,517 longitudinal QT interval measurements, uncovering 9 novel variants, most replicating in 40,537 individuals in the UK Biobank and Population Architecture using Genomics and Epidemiology studies. A meta-analysis of all 3 cohorts (n = 117,532) uncovered an additional 19 novel variants. Conditional analysis identified 15 additional variants, 3 of which were novel. Little, if any, difference was seen when adjusting for putative QT interval lengthening medications genome-wide. Using multiple measurements in Genetic Epidemiology Research on Adult Health and Aging increased variance explained by 163%, and we show that the ≈6 measurements in Genetic Epidemiology Research on Adult Health and Aging was equivalent to a 2.4× increase in sample size of a design with a single measurement. The array heritability was estimated at ≈17%, approximately half of our estimate of 36% from family correlations. Heritability enrichment was estimated highest and most significant in cardiovascular tissue (enrichment 7.2, 95% CI = 5.7-8.7, P = 2.1e-10), and many of the novel variants included expression quantitative trait loci in heart and other relevant tissues. Comparing our results to other cardiac function traits, it appears that QT interval has a multifactorial genetic etiology.

Authors: Hoffmann TJ; Lu M; Oni-Orisan A; Lee C; Risch N; Iribarren C | November 30, 2022 | PubMed abstract

This study examined the relationship between maternal food source and preparation during pregnancy and the duration of breastfeeding among 751 mother-child dyads in the United States. The data collected from the Environmental influences on Child Health Outcomes (ECHO) Program included twelve cohorts of mothers (age ≥ 18) who delivered infant(s). Three categories of maternal food source and preparation including, High, Moderate, or Low Food Source Quality were derived from the mother report. The mean duration of breastfeeding differed strongly across the three categories. The High Food Source Quality group breastfed an average of 41 weeks, while shorter durations were observed for the Moderate (26 weeks) and Low (16 weeks) Food Source Quality groups. Cox proportional hazards models were used to estimate the relative hazard of time to breastfeeding cessation for each participant characteristic. The full model adjusted for clustering/cohort effect for all participant characteristics, while the final model adjusted for the subset of characteristics identified from variable reduction modeling. The hazard of breastfeeding cessation for those in the High Food Source Quality group was 24% less than the Moderate group (RH = 0.76; 95% CI, 0.63-0.92). Pregnant women in the High Food Source Quality group breastfed longer than the Moderate and Low groups. We encourage more detailed studies in the future to examine this relationship longitudinally.

Authors: Zimmerman E; Gachigi KK; Rodgers RF; Watkins DJ; Woodbury M; Cordero JF; Alshawabkeh A; Meeker JD; Huerta-Montañez G; Pabon ZR; Hines M; Velez-Vega CM; Camargo CA; Zhu Y; Nozadi SS; Comstock SS; Hockett C; Tarwater PM; On Behalf Of Program Collaborators For Environmental Influences On Child Health Outcomes | November 21, 2022 | PubMed abstract

Genetic substudies of randomized controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction; it is unknown if the association extends to statin users undergoing routine care. We sought to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of participants without previous myocardial infarction. We determined CHD polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Covariate-adjusted Cox regression models were used to compare the risk of cardiovascular outcomes between statin users and matched nonusers. Statin effectiveness on incident myocardial infarction showed no gradient with increasing 10-year Pooled Cohort Equations atherosclerotic cardiovascular disease (ASCVD) risk across low, borderline, intermediate, and high ASCVD risk score groups. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (hazard ratio (HR) 0.41, 95% confidence interval (CI), 0.31-0.53; P = 1.5E-11), intermediate in the intermediate polygenic risk score group (HR 0.56, 95% CI, 0.47-0.66; P = 8.4E-12), and smallest in the low polygenic risk score group (HR 0.67, 95% CI, 0.47-0.97; P = 0.03; P for high vs. low = 0.01). ASCVD risk and statin low-density lipoprotein cholesterol (LDL-C) lowering did not differ across polygenic risk score groups. In patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of LDL-C lowering. Our findings extend prior work by identifying a subset (i.e., self-identified White individuals with low CHD polygenic risk scores) with attenuated clinical benefit from statins.

Authors: Oni-Orisan A; Haldar T; Cayabyab MAS; Ranatunga DK; Hoffmann TJ; Iribarren C; Krauss RM; Risch N | November 1, 2022 | PubMed abstract

Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.

Authors: Cavazos TB; Kachuri L; Graff RE; Nierenberg JL; Thai KK; Alexeeff S; Van Den Eeden S; Corley DA; Kushi LH; Regeneron Genetics Center; Hoffmann TJ; Ziv E; Habel LA; Jorgenson E; Sakoda LC; Witte JS | October 6, 2022 | PubMed abstract

Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.

Authors: Praveen, Kavita; Patel, Gaurang C.; Gurski, Lauren; Ayer, Ariane H.; Persaud, Trikaladarshi; Still, Matthew D.; Miloscio, Lawrence; Van Zyl, Tavé; Di Gioia, Silvio Alessandro; Brumpton, Ben; Krebs, Kristi; Åsvold, Bjørn Olav; Chen, Esteban; Chavali, Venkata R. M.; Fury, Wen; Gudiseva, Harini V.; Hyde, Sarah; Jorgenson, Eric; Lefebvre, Stephanie; Li, Dadong; Li, Alexander; Mclninch, James; Patel, Brijeshkumar; Rabinowitz, Jeremy S.; Salowe, Rebecca; Schurmann, Claudia; Seidelin, Anne-Sofie; Stahl, Eli; Sun, Dylan; Teslovich, Tanya M.; Tybjærg-Hansen, Anne; Willer, Cristen; Waldron, Scott; Walley, Sabrina; Yang, Hua; Zaveri, Sarthak; Regeneron Genetics Center; GHS-RGC DiscovEHR Collaboration; Estonian Biobank Research Team; Hu, Ying; Hveem, Kristian; Melander, Olle; Milani, Lili; Stender, Stefan; O'Brien, Joan M.; Jones, Marcus B.; Abecasis, Gonçalo R.; Cantor, Michael N.; Weyne, Jonathan; Karalis, Katia; Economides, Aris; Della Gatta, Giusy; Ferreira, Manuel A.; Yancopoulos, George D.; Baras, Aris; Romano, Carmelo; Coppola, Giovanni | October 3, 2022 | PubMed abstract

Experts hypothesized increased weight gain in children associated with the coronavirus disease 2019 (COVID-19) pandemic. Our objective was to evaluate whether the rate of change of child body mass index (BMI) increased during the COVID-19 pandemic compared with prepandemic years. The study population of 1996 children ages 2 to 19 years with at least 1 BMI measure before and during the COVID-19 pandemic was drawn from 38 pediatric cohorts across the United States participating in the Environmental Influences on Child Health Outcomes-wide cohort study. We modeled change in BMI using linear mixed models, adjusting for age, sex, race, ethnicity, maternal education, income, baseline BMI category, and type of BMI measure. Data collection and analysis were approved by the local institutional review board of each institution or by the central Environmental Influences on Child Health Outcomes institutional review board. BMI increased during the COVID-19 pandemic compared with previous years (0.24 higher annual gain in BMI during the pandemic compared with previous years, 95% confidence interval 0.02 to 0.45). Children with BMI in the obese range compared with the healthy weight range were at higher risk for excess BMI gain during the pandemic, whereas children in higher-income households were at decreased risk of BMI gain. One effect of the COVID-19 pandemic is an increase in annual BMI gain during the COVID-19 pandemic compared with the 3 previous years among children in our national cohort. This increased risk among US children may worsen a critical threat to public health and health equity.

Authors: Knapp EA; Dong Y; Dunlop AL; Aschner JL; Stanford JB; Hartert T; Teitelbaum SL; Hudak ML; Carroll K; O'Connor TG; McEvoy CT; O'Shea TM; Carnell S; Karagas MR; Herbstman JB; Dabelea D; Ganiban JM; Ferrara A; Hedderson M; Bekelman TA; Rundle AG; Alshawabkeh A; Gilbert-Diamond D; Fry RC; Chen Z; Gilliland FD; Wright RJ; Camargo CA; Jacobson L; Lester BM; Hockett CW; Hodges ML; Chandran A; Environmental Influences on Child Health Outcomes | September 1, 2022 | PubMed abstract

Refractive error (RE) is the most common form of visual impairment, and myopic RE is associated with an increased risk of primary open-angle glaucoma (POAG). Whether this association represents a causal role of RE in the etiology of POAG remains unknown. To evaluate shared genetic influences and investigate the association of myopic RE with the risk for POAG. Observational analyses were used to evaluate the association between mean spherical equivalent (MSE) RE (continuous trait) or myopia (binary trait) and POAG risk in individuals from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. To quantify genetic overlap, genome-wide genetic correlation analyses were performed using genome-wide association studies (GWAS) of MSE RE or myopia and POAG from GERA. Potential causal effects were assessed between MSE RE and POAG using 2-sample Mendelian randomization. Genetic variants associated with MSE RE were derived using GWAS summary statistics from a GWAS of RE conducted in 102 117 UK Biobank participants. For POAG, we used GWAS summary statistics from our previous GWAS (3836 POAG cases and 48 065 controls from GERA). Data analyses occurred between July 2020 and October 2021. Our main outcome was POAG risk as odds ratio (OR) caused by per-unit difference in MSE RE (in diopters). Our observational analyses included data for 54 755 non-Hispanic White individuals (31 926 [58%] females and 22 829 [42%] males). Among 4047 individuals with POAG, mean (SD) age was 73.64 (9.20) years; mean (SD) age of the 50 708 controls was 65.38 (12.24) years. Individuals with POAG had a lower refractive MSE and were more likely to have myopia or high myopia compared with the control participants (40.2% vs 34.1%, P = 1.31 × 10-11 for myopia; 8.5% vs 6.8%, P = .004 for high myopia). Our genetic correlation analyses demonstrated that POAG was genetically correlated with MSE RE (rg, -0.24; SE, 0.06; P = 3.90 × 10-5), myopia (rg, 0.21; SE, 0.07; P = .004), and high myopia (rg, 0.23; SE, 0.09; P = .01). Genetically assessed refractive MSE was negatively associated with POAG risk (inverse-variance weighted model: OR per diopter more hyperopic MSE = 0.94; 95% CI, 0.89-0.99; P = .01). These findings demonstrate a shared genetic basis and an association between myopic RE and POAG risk. This may support population POAG risk stratification and screening strategies, based on RE information.

Authors: Choquet H; Khawaja AP; Jiang C; Yin J; Melles RB; Glymour MM; Hysi PG; Jorgenson E | September 1, 2022 | PubMed abstract

Literature shows lower dementia incidence in Asian American groups versus whites, varying by Asian ethnicity. One hypothesized driver is nativity differences (eg, healthy immigrant effect). We followed a cohort of 6243 Chinese, 4879 Filipino, 3256 Japanese, and 141,158 white Kaiser Permanente Northern California members for incident dementia (2002 to 2020), estimating age-adjusted dementia incidence rates by ethnicity and nativity, and hazard ratios (HR) for nativity on dementia incidence using ethnicity-stratified age- and sex-adjusted Cox proportional hazards models. Dementia incidence appeared higher in foreign- versus US-born Filipinos (HR, 95% confidence interval: 1.39, 1.02 to 1.89); differences were small in Japanese (1.07, 0.88 to 1.30) and Chinese (1.07, 0.92 to 1.24). No nativity differences were observed among whites (1.00, 0.95 to 1.04). Nativity does not explain lower dementia incidence in Asian Americans versus whites, but may contribute to heterogeneity across Asian ethnicities. Future research should explore differential impacts of social and cardiometabolic factors.

Authors: Hayes-Larson E; Fong J; Mobley TM; Gilsanz P; Whitmer RA; Gee GC; Brookmeyer R; Mayeda ER | August 1, 2022 | PubMed abstract

The chr12q24.13 locus encoding OAS1-OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454 -A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

Authors: Banday AR; Stanifer ML; Florez-Vargas O; Onabajo OO; Papenberg BW; Zahoor MA; Mirabello L; Ring TJ; Lee CH; Albert PS; Andreakos E; Arons E; Barsh G; Biesecker LG; Boyle DL; Brahier MS; Burnett-Hartman A; Carrington M; Chang E; Choe PG; Chisholm RL; Colli LM; Dalgard CL; Dude CM; Edberg J; Erdmann N; Feigelson HS; Fonseca BA; Firestein GS; Gehring AJ; Guo C; Ho M; Holland S; Hutchinson AA; Im H; Irby L; Ison MG; Joseph NT; Kim HB; Kreitman RJ; Korf BR; Lipkin SM; Mahgoub SM; Mohammed I; Paschoalini GL; Pacheco JA; Peluso MJ; Rader DJ; Redden DT; Ritchie MD; Rosenblum B; Ross ME; Anna HPS; Savage SA; Sharma S; Siouti E; Smith AK; Triantafyllia V; Vargas JM; Vargas JD; Verma A; Vij V; Wesemann DR; Yeager M; Yu X; Zhang Y; Boulant S; Chanock SJ; Feld JJ; Prokunina-Olsson L | August 1, 2022 | PubMed abstract

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

Authors: Byun J; Han Y; Li Y; Xia J; Long E; Choi J; Xiao X; Zhu M; Zhou W; Sun R; Bossé Y; Song Z; Schwartz A; Lusk C; Rafnar T; Stefansson K; Zhang T; Zhao W; Pettit RW; Liu Y; Li X; Zhou H; Walsh KM; Gorlov I; Gorlova O; Zhu D; Rosenberg SM; Pinney S; Bailey-Wilson JE; Mandal D; de Andrade M; Gaba C; Willey JC; You M; Anderson M; Wiencke JK; Albanes D; Lam S; Tardon A; Chen C; Goodman G; Bojeson S; Brenner H; Landi MT; Chanock SJ; Johansson M; Muley T; Risch A; Wichmann HE; Bickeböller H; Christiani DC; Rennert G; Arnold S; Field JK; Shete S; Le Marchand L; Melander O; Brunnstrom H; Liu G; Andrew AS; Kiemeney LA; Shen H; Zienolddiny S; Grankvist K; Johansson M; Caporaso N; Cox A; Hong YC; Yuan JM; Lazarus P; Schabath MB; Aldrich MC; Patel A; Lan Q; Rothman N; Taylor F; Kachuri L; Witte JS; Sakoda LC; Spitz M; Brennan P; Lin X; McKay J; Hung RJ; Amos CI | August 1, 2022 | PubMed abstract

To examine postpartum depressive symptom trajectories from birth to age 5 and their risk factors in a national sample of mothers of preterm and full-term infants. The racially and ethnically diverse sample comprised 11,320 maternal participants (Mage = 29; SD = 5.9) in the Environmental influences on Child Health Outcomes (ECHO) Program in the USA with data on newborn gestational age at birth (≥ 22 weeks) and maternal depression symptoms during the first 5 years following childbirth. Growth mixture models determined the number and trajectory of postpartum depression classes among women in the preterm and full-term groups, and we examined predictors of class membership. Five trajectories described depressive symptoms for both groups; however, notable differences were observed. One in 5 mothers of preterm infants developed clinically relevant depressive symptoms over time compared with 1 in 10 mothers of full-term infants. Among women who delivered preterm compared with those who delivered full-term, symptoms were more likely to increase over time and become severe when offspring were older. Distinct subgroups describe mothers’ depressive symptom trajectories through 5 years following childbirth. Mild to moderate depressive symptoms may onset or persist for many women beyond the initial postpartum period regardless of newborn gestational age at birth. For women with preterm infants, initially mild symptoms may increase to high levels of severity during the preschool and toddler years.

Authors: Roubinov, Danielle; Musci, Rashelle J.; Hipwell, Alison E.; Wu, Guojing; Santos, Hudson; Felder, Jennifer N.; Faleschini, Sabrina; Conradt, Elisabeth; McEvoy, Cindy T.; Lester, Barry M.; Buss, Claudia; Elliott, Amy J.; Cordero, José F.; Stroustrup, Annemarie; Bush, Nicole R. | August 1, 2022 | PubMed abstract

Prior studies of the glycemic effect of statins have been inconsistent. Also, most studies have only considered a short duration of statin use; the effect of long-term statin use on fasting glucose (FG) has not been well examined. The aim of this work is to investigate the effect of long-term statin exposure on FG levels. Using electronic health record (EHR) data from a large and diverse longitudinal cohort, we defined long-term statin exposure in two ways: the cumulative years of statin use (cumulative supply) and the years’ supply-weighted sum of doses (cumulative dose). Simvastatin, lovastatin, atorvastatin and pravastatin were included in the analysis. The relationship between statin exposure and FG was examined using linear regression with mixed effects modeling, comparing statin users before and after initiating statins and statin never-users. We examined 593,130 FG measurements from 87,151 individuals over a median follow up of 20 years. Of these, 42,678 were never-users and 44,473 were statin users with a total of 730,031 statin prescriptions. FG was positively associated with cumulative supply of statin but not comulative dose when both measures were in the same model. While statistically significant, the annual increase in FG attributable to statin exposure was modest at only 0.14 mg/dl, with only slight and non-significant differences among statin types. Elevation in FG level is associated with statin exposure, but the effect is modest. The results suggest that the risk of a clinically significant increase in FG attributable to long-term statin use is small for most individuals.

Authors: Haldar T; Oni-Orisan A; Hoffmann TJ; Schaefer C; Iribarren C; Krauss RM; Medina MW; Risch N | July 14, 2022 | PubMed abstract

Inguinal hernias are some of the most frequently diagnosed conditions in clinical practice and inguinal hernia repair is the most common procedure performed by general surgeons. Studies of inguinal hernias in non-European populations are lacking, though it is expected that such studies could identify novel loci. Further, the cumulative lifetime incidence of inguinal hernia is nine times greater in men than women, however, it is not clear why this difference exists. We conducted a genome-wide association meta-analysis of inguinal hernia risk across 513 120 individuals (35 774 cases and 477 346 controls) of Hispanic/Latino, African, Asian and European descent, with replication in 728 418 participants (33 491 cases and 694 927 controls) from the 23andMe, Inc dataset. We identified 63 genome-wide significant loci (P < 5 × 10-8), including 41 novel. Ancestry-specific analyses identified two loci (LYPLAL1-AS1/SLC30A10 and STXBP6-NOVA1) in African ancestry individuals. Sex-stratified analyses identified two loci (MYO1D and ZBTB7C) that are specific to women, and four (EBF2, EMX2/RAB11FIP2, VCL and FAM9A/FAM9B) that are specific to men. Functional experiments demonstrated that several of the associated regions (EFEMP1 and LYPLAL1-SLC30A10) function as enhancers and show differential activity between risk and reference alleles. Our study highlights the importance of large-scale genomic studies in ancestrally diverse populations for identifying ancestry-specific inguinal hernia susceptibility loci and provides novel biological insights into inguinal hernia etiology.

Authors: Choquet H; Li W; Yin J; Bradley R; Hoffmann TJ; Nandakumar P; 23 and Me Research Team; Mostaedi R; Tian C; Ahituv N; Jorgenson E | July 7, 2022 | PubMed abstract

Limited studies examine how prenatal environmental and social exposures jointly impact perinatal health. Here we investigated relationships between a neighborhood-level combined exposure (CE) index assessed during pregnancy and perinatal outcomes, including birthweight, gestational age, and preterm birth. Across all participants, higher CE index scores were associated with small decreases in birthweight and gestational age. We also observed effect modification by race; infants born to Black pregnant people had a greater risk of preterm birth for higher CE values compared to White infants. Overall, our results suggest that neighborhood social and environmental exposures have a small but measurable joint effect on neonatal indicators of health.

Authors: Martenies SE; Zhang M; Corrigan AE; Kvit A; Shields T; Wheaton W; Bastain TM; Breton CV; Dabelea D; Habre R; Magzamen S; Padula AM; Him DA; Camargo CA; Cowell W; Croen LA; Deoni S; Everson TM; Hartert TV; Hipwell AE; McEvoy CT; Morello-Frosch R; O'Connor TG; Petriello M; Sathyanarayana S; Stanford JB; Woodruff TJ; Wright RJ; Kress AM; program collaborators for Environmental influences on Child Health Outcomes | July 1, 2022 | PubMed abstract

To identify genetic variants associated with pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) in unrelated patients and to further understand the genetic and potentially causal relationships between PDS and associated risk factors. A 2-stage genome-wide association meta-analysis with replication and subsequent in silico analyses including Mendelian randomization. A total of 574 cases with PG or PDS and 52 627 controls of European descent. Genome-wide association analyses were performed in 4 cohorts and meta-analyzed in 3 stages: (1) a discovery meta-analysis was performed in 3 cohorts, (2) replication was performed in the fourth cohort, and (3) all 4 cohorts were meta-analyzed to increase statistical power. Two-sample Mendelian randomization was used to determine whether refractive error and intraocular pressure exert causal effects over PDS. The association of genetic variants with PDS and whether myopia exerts causal effects over PDS. Significant association was present at 2 novel loci for PDS/PG. These loci and follow-up analyses implicate the genes gamma secretase activator protein (GSAP) (lead single nucleotide polymorphism [SNP]: rs9641220, P = 6.0×10-10) and glutamate metabotropic receptor 5 (GRM5)/TYR (lead SNP: rs661177, P = 3.9×10-9) as important factors in disease risk. Mendelian randomization showed significant evidence that negative refractive error (myopia) exerts a direct causal effect over PDS (P = 8.86×10-7). Common SNPs relating to the GSAP and GRM5/TYR genes are associated risk factors for the development of PDS and PG. Although myopia is a known risk factor, this study uses genetic data to demonstrate that myopia is, in part, a cause of PDS and PG.

Authors: Simcoe MJ; Shah A; Fan B; Choquet H; Weisschuh N; Waseem NH; Jiang C; Melles RB; Ritch R; Mahroo OA; Wissinger B; Jorgenson E; Wiggs JL; Garway-Heath DF; Hysi PG; Hammond CJ | June 1, 2022 | PubMed abstract

Broad participation in genetic research is needed to promote equitable advances in disease treatment and prevention. The objective of the study was to assess motivations for, and concerns about, genetic research participation. The Genetics in Research and Health Care Survey was sent in winter 2017-2018 to 57,331 adult Kaiser Permanente (KP) members from 7 US regions to assess attitudes about genetic testing in health care and research. The survey included an open-ended question on why members would or would not participate in genetic research. Open text responses to this question were coded in the qualitative analysis software Dedoose and analyzed using a thematic analysis approach. Code summaries were organized by major themes, subthemes, and exemplary quotes. Of the 10,369 participants who completed the survey, 2,645 (25%) provided a comment describing reasons they would or would not participate in research involving genetic testing. Respondents who provided a text comment were 64% female, 49% non-Hispanic (NH) White, 17% Asian/Pacific Islander, 20% Hispanic, and 14% NH Black. The primary themes identified were (1) altruism; (2) decision-making and planning; (3) data use; and (4) data security. These major themes were consistent across each race and ethnic group. To promote broad participation in genetic research, it is important that recruitment materials address the primary motivators for genetic research participation, including altruism and the potential use of results for personal decision-making. Study materials should also address concerns about possible misuse of genetic information and fears over potential data breaches.

Authors: Madrid SD; Blum-Barnett E; Lemke AA; Pan V; Paolino V; McGlynn EA; Burnett-Hartman AN | May 11, 2022 | PubMed abstract

Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Authors: John C; Guyatt AL; Shrine N; Packer R; Olafsdottir TA; Liu J; Hayden LP; Chu SH; Koskela JT; Luan J; Li X; Terzikhan N; Xu H; Bartz TM; Petersen H; Leng S; Belinsky SA; Cepelis A; Hernández Cordero AI; Obeidat M; Thorleifsson G; Meyers DA; Bleecker ER; Sakoda LC; Iribarren C; Tesfaigzi Y; Gharib SA; Dupuis J; Brusselle G; Lahousse L; Ortega VE; Jonsdottir I; Sin DD; Bossé Y; van den Berge M; Nickle D; Quint JK; Sayers I; Hall IP; Langenberg C; Ripatti S; Laitinen T; Wu AC; Lasky-Su J; Bakke P; Gulsvik A; Hersh CP; Hayward C; Langhammer A; Brumpton B; Stefansson K; Cho MH; Wain LV; Tobin MD | May 1, 2022 | PubMed abstract

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD’s polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Authors: Palmer DS; Howrigan DP; Chapman SB; Adolfsson R; Bass N; Blackwood D; Boks MPM; Chen CY; Churchhouse C; Corvin AP; Craddock N; Curtis D; Di Florio A; Dickerson F; Freimer NB; Goes FS; Jia X; Jones I; Jones L; Jonsson L; Kahn RS; Landén M; Locke AE; McIntosh AM; McQuillin A; Morris DW; O'Donovan MC; Ophoff RA; Owen MJ; Pedersen NL; Posthuma D; Reif A; Risch N; Schaefer C; Scott L; Singh T; Smoller JW; Solomonson M; Clair DS; Stahl EA; Vreeker A; Walters JTR; Wang W; Watts NA; Yolken R; Zandi PP; Neale BM | May 1, 2022 | PubMed abstract

Actinic keratosis (AK) is a common precancerous cutaneous neoplasm that arises on chronically sun-exposed skin. AK susceptibility has a moderate genetic component, and although a few susceptibility loci have been identified, including IRF4, TYR, and MC1R, additional loci have yet to be discovered. We conducted a genome-wide association study of AK in non-Hispanic white participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (n = 63,110, discovery cohort), with validation in the Mass-General Brigham (MGB) Biobank cohort (n = 29,130). We identified eleven loci (P < 5 × 10-8), including seven novel loci, of which four novel loci were validated. In a meta-analysis (GERA + MGB), one additional novel locus, TRPS1, was identified. Genes within the identified loci are implicated in pigmentation (SLC45A2, IRF4, BNC2, TYR, DEF8, RALY, HERC2, and TRPS1), immune regulation (FOXP1 and HLA-DQA1), and cell signaling and tissue remodeling (MMP24) pathways. Our findings provide novel insight into the genetics and pathogenesis of AK susceptibility.

Authors: Kim Y; Yin J; Huang H; Jorgenson E; Choquet H; Asgari MM | April 21, 2022 | PubMed abstract

Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

Authors: Chen H; Fan S; Stone J; Thompson DJ; Douglas J; Li S; Scott C; Bolla MK; Wang Q; Dennis J; Michailidou K; Li C; Peters U; Hopper JL; Southey MC; Nguyen-Dumont T; Nguyen TL; Fasching PA; Behrens A; Cadby G; Murphy RA; Aronson K; Howell A; Astley S; Couch F; Olson J; Milne RL; Giles GG; Haiman CA; Maskarinec G; Winham S; John EM; Kurian A; Eliassen H; Andrulis I; Evans DG; Newman WG; Hall P; Czene K; Swerdlow A; Jones M; Pollan M; Fernandez-Navarro P; McConnell DS; Kristensen VN; NBCS Investigators; Rothstein JH; Wang P; Habel LA; Sieh W; Dunning AM; Pharoah PDP; Easton DF; Gierach GL; Tamimi RM; Vachon CM; Lindström S | April 12, 2022 | PubMed abstract

The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants. Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve. Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores. Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.

Authors: Archambault AN; Jeon J; Lin Y; Thomas M; Harrison TA; Bishop DT; Brenner H; Casey G; Chan AT; Chang-Claude J; Figueiredo JC; Gallinger S; Gruber SB; Gunter MJ; Guo F; Hoffmeister M; Jenkins MA; Keku TO; Le Marchand L; Li L; Moreno V; Newcomb PA; Pai R; Parfrey PS; Rennert G; Sakoda LC; Lee JK; Slattery ML; Song M; Win AK; Woods MO; Murphy N; Campbell PT; Su YR; Lansdorp-Vogelaar I; Peterse EFP; Cao Y; Zeleniuch-Jacquotte A; Liang PS; Du M; Corley DA; Hsu L; Peters U; Hayes RB | April 11, 2022 | PubMed abstract

The family stress model proposes economic hardship results in caregiver distress and relational problems, which negatively impact youth outcomes. We extend this model to evaluate the impact of coronavirus disease 2019 pandemic-related family hardships on caregiver and youth stress, and, in turn, youth’s psychological well-being. We also investigate how social supports moderate this relationship. We used 2 samples of cross-sectional survey data collected between May 2020 and May 2021: children aged 2 to 12 years (n = 977) and adolescents aged 11 to 17 years (n = 669). Variables included pandemic-related family hardships, stress, social support, and youth life satisfaction. Data were analyzed using structural equation modeling. Experiencing more pandemic-related family hardships was associated with increased caregiver and youth stress (b = 0.04 to 0.21, SE = 0.01-0.02) and, in turn, decreased youth life satisfaction (b = -0.36 to -0.38, SE = 0.04-0.07). Social connectedness (b^ = 0.11-0.17, SE = 0.04) and family engagement (b^ = 0.12-0.18, SE = 0.05-0.06) had direct positive associations with life satisfaction; for children aged 2 to 12 years, greater family engagement was associated with decreased effect of child stress on life satisfaction (b^ = 0.15, SE = 0.05). For adolescents, females had higher levels of stress compared with males (b^ = 0.40, SE = 0.6), and having anxiety and/or depression was associated with decreased life satisfaction (b^ = -0.24, SE = 0.11). Caregivers and youth who experienced more coronavirus disease 2019 pandemic hardships had higher levels of stress, particularly adolescent females. Although stress negatively impacted life satisfaction across all ages, family engagement was a protective factor for children aged 2 to 12 years, whereas having anxiety and/or depression was a risk factor for adolescents. For all youth, however, being more socially connected and engaged with family promoted life satisfaction.

Authors: Blackwell CK; Mansolf M; Sherlock P; Ganiban J; Hofheimer JA; Barone CJ; Bekelman TA; Blair C; Cella D; Collazo S; Croen LA; Deoni S; Elliott AJ; Ferrara A; Fry RC; Gershon R; Herbstman JB; Karagas MR; LeWinn KZ; Margolis A; Miller RL; O'Shea TM; Porucznik CA; Wright RJ | April 1, 2022 | PubMed abstract

Few germline genetic variants have been robustly linked with breast cancer outcomes. We conducted trans-ethnic meta genome-wide association study (GWAS) of overall survival (OS) in 3973 breast cancer patients from the Pathways Study, one of the largest prospective breast cancer survivor cohorts. A locus spanning the UACA gene, a key regulator of tumor suppressor Par-4, was associated with OS in patients taking Par-4 dependent chemotherapies, including anthracyclines and anti-HER2 therapy, at a genome-wide significance level ([Formula: see text]). This association was confirmed in meta-analysis across four independent prospective breast cancer cohorts (combined hazard ratio = 1.84, [Formula: see text]). Transcriptome-wide association study revealed higher UACA gene expression was significantly associated with worse OS ([Formula: see text]). Our study identified the UACA locus as a genetic predictor of patient outcome following treatment with anthracyclines and/or anti-HER2 therapy, which may have clinical utility in formulating appropriate treatment strategies for breast cancer patients based on their genetic makeup.

Authors: Zhu Q; Schultz E; Long J; Roh JM; Valice E; Laurent CA; Radimer KH; Yan L; Ergas IJ; Davis W; Ranatunga D; Gandhi S; Kwan ML; Bao PP; Zheng W; Shu XO; Ambrosone C; Yao S; Kushi LH | March 23, 2022 | PubMed abstract

Given inconsistent evidence on preconception or prenatal tobacco use and offspring autism spectrum disorder (ASD), this study assessed associations of maternal smoking with ASD and ASD-related traits. Among 72 cohorts in the Environmental Influences on Child Health Outcomes consortium, 11 had ASD diagnosis and prenatal tobaccosmoking (n = 8648). and 7 had Social Responsiveness Scale (SRS) scores of ASD traits (n = 2399). Cohorts had diagnoses alone (6), traits alone (2), or both (5). Diagnoses drew from parent/caregiver report, review of records, or standardized instruments. Regression models estimated smoking-related odds ratios (ORs) for diagnoses and standardized mean differences for SRS scores. Cohort-specific ORs were meta-analyzed. Overall, maternal smoking was unassociated with child ASD (adjusted OR, 1.08; 95% confidence interval [CI], 0.72-1.61). However, heterogeneity across studies was strong: preterm cohorts showed reduced ASD risk for exposed children. After excluding preterm cohorts (biased by restrictions on causal intermediate and exposure opportunity) and small cohorts (very few ASD cases in either smoking category), the adjusted OR for ASD from maternal smoking was 1.44 (95% CI, 1.02-2.03). Children of smoking (versus non-smoking) mothers had more ASD traits (SRS T-score + 2.37 points, 95% CI, 0.73-4.01 points), with results homogeneous across cohorts. Maternal preconception/prenatal smoking was consistently associated with quantitative ASD traits and modestly associated with ASD diagnosis among sufficiently powered United States cohorts of non-preterm children. Limitations resulting from self-reported smoking and unmeasured confounders preclude definitive conclusions. Nevertheless, counseling on potential and known risks to the child from maternal smoking is warranted for pregnant women and pregnancy planners. LAY SUMMARY: Evidence on the association between maternal prenatal smoking and the child’s risk for autism spectrum disorder has been conflicting, with some studies reporting harmful effects, and others finding reduced risks. Our analysis of children in the ECHO consortium found that maternal prenatal tobacco smoking is consistently associated with an increase in autism-related symptoms in the general population and modestly associated with elevated risk for a diagnosis of autism spectrum disorder when looking at a combined analysis from multiple studies that each included both pre- and full-term births. However, this study is not proof of a causal connection. Future studies to clarify the role of smoking in autism-like behaviors or autism diagnoses should collect more reliable data on smoking and measure other exposures or lifestyle factors that might have confounded our results.

Authors: Hertz-Picciotto I; Korrick SA; Ladd-Acosta C; Karagas MR; Lyall K; Schmidt RJ; Dunlop AL; Croen LA; Dabelea D; Daniels JL; Duarte CS; Fallin MD; Karr CJ; Lester B; Leve LD; Li Y; McGrath M; Ning X; Oken E; Sagiv SK; Sathyanaraya S; Tylavsky F; Volk HE; Wakschlag LS; Zhang M; O'Shea TM; Musci RJ; program collaborators for Environmental influences on Child Health Outcomes (ECHO) | March 1, 2022 | PubMed abstract

The Kaiser Permanente Research Bank (KPRB) is collecting biospecimens and surveys linked to electronic health records (EHR) from approximately 400,000 adult KP members. Within the KPRB, we developed a Cancer Cohort to address issues related to cancer survival, and to understand how genetic, lifestyle and environmental factors impact cancer treatment, treatment sequelae, and prognosis. We describe the Cancer Cohort design and implementation, describe cohort characteristics after 5 years of enrollment, and discuss future directions. Cancer cases are identified using rapid case ascertainment algorithms, linkage to regional or central tumor registries, and direct outreach to KP members with a history of cancer. Enrollment is primarily through email invitation. Participants complete a consent form, survey, and donate a blood or saliva sample. All cancer types are included. As of December 31, 2020, the cohort included 65,225 cases (56% female, 44% male) verified in tumor registries. The largest group was diagnosed between 60 and 69 years of age (31%) and are non-Hispanic White (83%); however, 10,076 (16%) were diagnosed at ages 18-49 years, 4208 (7%) are Hispanic, 3393 (5%) are Asian, and 2389 (4%) are Black. The median survival time is 14 years. Biospecimens are available on 98% of the cohort. The KPRB Cancer Cohort is designed to improve our understanding of treatment efficacy and factors that contribute to long-term cancer survival. The cohort’s diversity – with respect to age, race/ethnicity and geographic location – will facilitate research on factors that contribute to cancer survival disparities.

Authors: Feigelson HS; Clarke CL; Van Den Eeden SK; Weinmann S; Burnett-Hartman AN; Rowell S; Scott SG; White LL; Ter-Minassian M; Honda SAA; Young DR; Kamineni A; Chinn T; Lituev A; Bauck A; McGlynn EA | February 25, 2022 | PubMed abstract

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI’s Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

Authors: Little A; Hu Y; Sun Q; Jain D; Broome J; Chen MH; Thibord F; McHugh C; Surendran P; Blackwell TW; Brody JA; Bhan A; Chami N; de Vries PS; Ekunwe L; Heard-Costa N; Hobbs BD; Manichaikul A; Moon JY; Preuss MH; Ryan K; Wang Z; Wheeler M; Yanek LR; Abecasis GR; Almasy L; Beaty TH; Becker LC; Blangero J; Boerwinkle E; Butterworth AS; Choquet H; Correa A; Curran JE; Faraday N; Fornage M; Glahn DC; Hou L; Jorgenson E; Kooperberg C; Lewis JP; Lloyd-Jones DM; Loos RJF; Min YI; Mitchell BD; Morrison AC; Nickerson DA; North KE; O'Connell JR; Pankratz N; Psaty BM; Vasan RS; Rich SS; Rotter JI; Smith AV; Smith NL; Tang H; Tracy RP; Conomos MP; Laurie CA; Mathias RA; Li Y; Auer PL; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Thornton T; Reiner AP; Johnson AD; Raffield LM | February 3, 2022 | PubMed abstract

Hematological measures are important intermediate clinical phenotypes for many acute and chronic diseases and are highly heritable. Although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, the causal genes underlying these associations are often uncertain. To better understand the underlying genetic regulatory mechanisms, we performed a transcriptome-wide association study (TWAS) to systematically investigate the association between genetically predicted gene expression and hematological measures in 54,542 Europeans from the Genetic Epidemiology Research on Aging cohort. We found 239 significant gene-trait associations with hematological measures; we replicated 71 associations at p < 0.05 in a TWAS meta-analysis consisting of up to 35,900 Europeans from the Women's Health Initiative, Atherosclerosis Risk in Communities Study, and BioMe Biobank. Additionally, we attempted to refine this list of candidate genes by performing conditional analyses, adjusting for individual variants previously associated with hematological measures, and performed further fine-mapping of TWAS loci. To facilitate interpretation of our findings, we designed an R Shiny application to interactively visualize our TWAS results by integrating them with additional genetic data sources (GWAS, TWAS from multiple reference panels, conditional analyses, known GWAS variants, etc.). Our results and application highlight frequently overlooked TWAS challenges and illustrate the complexity of TWAS fine-mapping.

Authors: Tapia AL; Rowland BT; Rosen JD; Preuss M; Young K; Graff M; Choquet H; Couper DJ; Buyske S; Bien SA; Jorgenson E; Kooperberg C; Loos RJF; Morrison AC; North KE; Yu B; Reiner AP; Li Y; Raffield LM | February 1, 2022 | PubMed abstract

TdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia. Our goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real-world healthcare setting. Case-control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow-up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018. A total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non-white. The independent predictors of TdP were potassium concentration <3.6 mEq/L (OR = 10.6), prior history of atrial fibrillation/flutter (OR = 6.2), QTc >480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in-hospital and 1-year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively. These findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.

Authors: Mantri N; Lu M; Zaroff JG; Risch N; Hoffmann T; Oni-Orisan A; Lee C; Iribarren C | January 1, 2022 | PubMed abstract

Stressors associated with COVID-19 pandemic stay-at-home orders are associated with increased depression and anxiety and decreased physical activity. Given that physical activity and time spent outdoors in nature are associated with improved mental health, we examined the longitudinal association of these variables during the pandemic. Over 20,000 adults who participated in the U.S. Kaiser Permanente Research Bank, did not report COVID-19 symptoms, and responded to an online baseline and 3 follow-up surveys over approximately 3 months formed the cohort. Physical activity was assessed from a modified survey, time spent outdoors was assessed from one question, and anxiety and depression scores were assessed from validated instruments. Almost 60% were women, 82.8% were non-Hispanic white, and more than 93% of respondents were over the age of 50. Less in-person contact with friends and visiting crowded places was highly prevalent (>80%) initially and decreased somewhat (>70%). Participants in the lowest physical activity category (no physical activity) had the highest depression and anxiety scores compared to each successive physical activity category (p < 0.001). Spending less time outdoors was associated with higher depression and anxiety scores. This effect was greater for participants in the younger age categories compared with older age categories. The effect of less time spent outdoors on anxiety (p = 0.012) and depression (p < 0.001) scores was smaller for males than females. Results suggest that physical activity and time outdoors is associated with better mental health. People should be encouraged to continue physical activity participation during public health emergencies.

Authors: Young DR; Hong BD; Lo T; Inzhakova G; Cohen DA; Sidell MA | January 1, 2022 | PubMed abstract

Although combustible cigarette use is an established risk factor for severe COVID-19 disease, there is conflicting evidence for the association of electronic cigarette use with SARS-CoV-2 infection and COVID-19 disease severity. Study participants were from the Kaiser Permanente Research Bank (KPRB), a biorepository that includes adult Kaiser Permanente members from across the United States. Starting in April 2020, electronic surveys were sent to KPRB members to assess the impact of the COVID-19 pandemic. These surveys collected information on self-report of SARS-CoV-2 infection and COVID-related risk factors, including electronic cigarette and combustible cigarette smoking history. We also used electronic health records data to assess COVID-19 diagnoses, positive PCR lab tests, hospitalizations, and death. We used multivariable Cox proportional hazards regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) comparing the risk of SARS-CoV-2 infection between individuals by e-cigarette use categories (never, former, and current). Among those with SARS-CoV-2 infection, we used multivariable logistic regression to estimate adjusted odds ratios (ORs) and 95% CIs comparing the odds of hospitalization or death within 30 days of infection between individuals by e-cigarette use categories. There were 126,475 individuals who responded to the survey and completed questions on e-cigarette and combustible cigarette use (48% response rate). Among survey respondents, 819 (1%) currently used e-cigarettes, 3,691 (3%) formerly used e-cigarettes, and 121,965 (96%) had never used e-cigarettes. After adjustment for demographic, behavioral, and clinical factors, there was no association with SARS-CoV-2 infection and former e-cigarette use (hazard ratio (HR) = 0.99; CI: 0.83-1.18) or current e-cigarette use (HR = 1.08; CI: 0.76-1.52). Among those with SARS-CoV-2 infection, there was no association with hospitalization or death within 30 days of infection and former e-cigarette use (odds ratio (OR) = 1.19; CI: 0.59-2.43) or current e-cigarette use (OR = 1.02; CI: 0.22-4.74). Our results suggest that e-cigarette use is not associated with an increased risk of SARS-CoV-2 infection or severe COVID-19 illness.

Authors: Burnett-Hartman AN; Goldberg Scott S; Powers JD; Clennin MN; Lyons JA; Gray M; Feigelson HS | January 1, 2022 | PubMed abstract

Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population-based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P < 0.005). In contrast, rs1134481 T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort. rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response.

Authors: Edris A; de Roos EW; McGeachie MJ; Verhamme KMC; Brusselle GG; Tantisira KG; Iribarren C; Lu M; Wu AC; Stricker BH; Lahousse L | January 1, 2022 | PubMed abstract

The aim of this study was to describe the association of individual-level characteristics (sex, race/ethnicity, birth weight, maternal education) with child BMI within each US Census region and variation in child BMI by region. This study used pooled data from 25 prospective cohort studies. Region of residence (Northeast, Midwest, South, West) was based on residential zip codes. Age- and sex-specific BMI z scores were the outcome. The final sample included 14,313 children with 85,428 BMI measurements, 49% female and 51% non-Hispanic White. Males had a lower average BMI z score compared with females in the Midwest (β = -0.12, 95% CI: -0.19 to -0.05) and West (β = -0.12, 95% CI: -0.20 to -0.04). Compared with non-Hispanic White children, BMI z score was generally higher among children who were Hispanic and Black but not across all regions. Compared with the Northeast, average BMI z score was significantly higher in the Midwest (β = 0.09, 95% CI: 0.05 to 0.14) and lower in the South (β = -0.12, 95% CI: -0.16 to -0.08) and West (β = -0.14, 95% CI: -0.19 to -0.09) after adjustment for age, sex, race/ethnicity, and birth weight. Region of residence was associated with child BMI z scores, even after adjustment for sociodemographic characteristics. Understanding regional influences can inform targeted efforts to mitigate BMI-related disparities among children.

Authors: Bekelman TA; Dabelea D; Ganiban JM; Law A; McGovern Reilly A; Althoff KN; Mueller N; Camargo CA; Duarte CS; Dunlop AL; Elliott AJ; Ferrara A; Gold DR; Hertz-Picciotto I; Hartert T; Hipwell AE; Huddleston K; Johnson CC; Karagas MR; Karr CJ; Hershey GKK; Leve L; Mahabir S; McEvoy CT; Neiderhiser J; Oken E; Rundle A; Sathyanarayana S; Turley C; Tylavsky FA; Watson SE; Wright R; Zhang M; Zoratti E; program collaborators for Environmental influences on Child Health Outcomes (ECHO) | December 1, 2021 | PubMed abstract

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

Authors: Mills, Melinda C.; Tropf, Felix C.; Brazel, David M.; van Zuydam, Natalie; Vaez, Ahmad; eQTLGen Consortium; BIOS Consortium; Human Reproductive Behaviour Consortium; Pers, Tune H.; Snieder, Harold; Perry, John R. B.; Ong, Ken K.; den Hoed, Marcel; Barban, Nicola; Day, Felix R. | December 1, 2021 | PubMed abstract

It is unknown why some athletes develop patellar tendinopathy and others do not, even when accounting for similar workloads between individuals. Genetic differences between these two populations may be a contributing factor. The purpose of this work was to screen the entire genome for genetic markers associated with patellar tendinopathy. Genome-wide association (GWA) analyses were performed utilizing data from the Kaiser Permanente Research Board (KPRB) and the UK Biobank. Patellar tendinopathy cases were identified based on electronic health records from KPRB and UK Biobank. GWA analyses from both cohorts were tested for patellar tendinopathy using a logistic regression model adjusting for sex, height, weight, age, and race/ethnicity using allele counts for single nucleotide polymorphisms. The data from the two GWA studies (KPRB and UK Biobank) were combined in a meta-analysis. There were a total of 1670 cases of patellar tendinopathy and 293,866 controls within the two cohorts. Two single nucleotide polymorphisms located in the intron of the cytochrome c oxidase assembly factor 1 (COA1) gene showed a genome-wide significant association in the meta-analysis. Genetic markers in COA1 seem to be associated with patellar tendinopathy and are potential risk factors for patellar tendinopathy that deserve further validation regarding molecular mechanisms.

Authors: Kim SK; Nguyen C; Horton BH; Avins AL; Abrams GD | November 1, 2021 | PubMed abstract

Polygenic risk scores (PRSs) will have important utility for asthma and other chronic diseases as a tool for predicting disease incidence and subphenotypes. We utilized findings from a large multiancestry GWAS of asthma to compute a PRS for asthma with relevance for racially diverse populations. We derived two PRSs for asthma using a standard approach (based on genome-wide significant variants) and a lasso sum regression approach (allowing all genetic variants to potentially contribute). We used data from the racially diverse Kaiser Permanente GERA cohort (68 638 non-Hispanic Whites, 5874 Hispanics, 6870 Asians and 2760 Blacks). Race was self-reported by questionnaire. For the standard PRS, non-Hispanic Whites showed the highest odds ratio for a standard deviation increase in PRS for asthma (OR = 1.16 (95% CI 1.14-1.18)). The standard PRS was also associated with asthma in Hispanic (OR = 1.12 (95% CI 1.05-1.19)) and Asian (OR = 1.10 (95% CI 1.04-1.17)) subjects, with a trend towards increased risk in Blacks (OR = 1.05 (95% CI 0.97-1.15)). We detected an interaction by sex, with men showing a higher risk of asthma with an increase in PRS as compared to women. The lasso sum regression-derived PRS showed stronger associations with asthma in non-Hispanic White subjects (OR = 1.20 (95% CI 1.18-1.23)), Hispanics (OR = 1.17 (95% 1.10-1.26)), Asians (OR = 1.18 (95% CI 1.10-1.27)) and Blacks (OR = 1.10 (95% CI 0.99-1.22)). Polygenic risk scores across multiple racial/ethnic groups were associated with increased asthma risk, suggesting that PRSs have potential as a tool for predicting disease development.

Authors: Sordillo JE; Lutz SM; Jorgenson E; Iribarren C; McGeachie M; Dahlin A; Tantisira K; Kelly R; Lasky-Su J; Sakornsakolpat P; Moll M; Cho MH; Wu AC | November 1, 2021 | PubMed abstract

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

Authors: Mikhaylova AV; McHugh CP; Polfus LM; Raffield LM; Boorgula MP; Blackwell TW; Brody JA; Broome J; Chami N; Chen MH; Conomos MP; Cox C; Curran JE; Daya M; Ekunwe L; Glahn DC; Heard-Costa N; Highland HM; Hobbs BD; Ilboudo Y; Jain D; Lange LA; Miller-Fleming TW; Min N; Moon JY; Preuss MH; Rosen J; Ryan K; Smith AV; Sun Q; Surendran P; de Vries PS; Walter K; Wang Z; Wheeler M; Yanek LR; Zhong X; Abecasis GR; Almasy L; Barnes KC; Beaty TH; Becker LC; Blangero J; Boerwinkle E; Butterworth AS; Chavan S; Cho MH; Choquet H; Correa A; Cox N; DeMeo DL; Faraday N; Fornage M; Gerszten RE; Hou L; Johnson AD; Jorgenson E; Kaplan R; Kooperberg C; Kundu K; Laurie CA; Lettre G; Lewis JP; Li B; Li Y; Lloyd-Jones DM; Loos RJF; Manichaikul A; Meyers DA; Mitchell BD; Morrison AC; Ngo D; Nickerson DA; Nongmaithem S; North KE; O'Connell JR; Ortega VE; Pankratz N; Perry JA; Psaty BM; Rich SS; Soranzo N; Rotter JI; Silverman EK; Smith NL; Tang H; Tracy RP; Thornton TA; Vasan RS; Zein J; Mathias RA; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Reiner AP; Auer PL | October 7, 2021 | PubMed abstract

Background Long QT has been associated with ventricular dysrhythmias, cardiovascular disease (CVD) mortality, and sudden cardiac death. However, no studies to date have investigated the dynamics of within-person QT change over time in relation to risk of incident CVD and all-cause mortality in a real-world setting. Methods and Results A cohort study among members of an integrated health care delivery system in Northern California including 61 455 people (mean age, 62 years; 60% women, 42% non-White) with 3 or more ECGs (baseline in 2005-2009; mean±SD follow-up time, 7.6±2.6 years). In fully adjusted models, tertile 3 versus tertile 1 of average QT corrected (using the Fridericia correction) was associated with cardiac arrest (hazard ratio [HR], 1.66), heart failure (HR, 1.62), ventricular dysrhythmias (HR, 1.56), all CVD (HR, 1.31), ischemic heart disease (HR, 1.28), total stroke (HR, 1.18), and all-cause mortality (HR, 1.24). Tertile 3 versus tertile 2 of the QT corrected linear slope was associated with cardiac arrest (HR, 1.22), ventricular dysrhythmias (HR, 1.12), and all-cause mortality (HR, 1.09). Tertile 3 versus tertile 1 of the QT corrected root mean squared error was associated with ventricular dysrhythmias (HR, 1.34), heart failure (HR, 1.28), all-cause mortality (HR, 1.20), all CVD (HR, 1.14), total stroke (HR, 1.08), and ischemic heart disease (HR, 1.07). Conclusions Our results demonstrate improved predictive ability for CVD outcomes using longitudinal information from serial ECGs. Long-term average QT corrected was more strongly associated with CVD outcomes than the linear slope or the root mean squared error. This new evidence is clinically relevant because ECGs are frequently used, noninvasive, and inexpensive.

Authors: Mantri N; Lu M; Zaroff JG; Risch N; Hoffmann T; Oni-Orisan A; Lee C; Jorgenson E; Iribarren C | October 5, 2021 | PubMed abstract

Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.

Authors: Julián-Serrano S; Yuan F; Wheeler W; Benyamin B; Machiela MJ; Arslan AA; Beane-Freeman LE; Bracci PM; Duell EJ; Du M; Gallinger S; Giles GG; Goodman PJ; Kooperberg C; Marchand LL; Neale RE; Shu XO; Van Den Eeden SK; Visvanathan K; Zheng W; Albanes D; Andreotti G; Ardanaz E; Babic A; Berndt SI; Brais LK; Brennan P; Bueno-de-Mesquita B; Buring JE; Chanock SJ; Childs EJ; Chung CC; Fabiánová E; Foretová L; Fuchs CS; Gaziano JM; Gentiluomo M; Giovannucci EL; Goggins MG; Hackert T; Hartge P; Hassan MM; Holcátová I; Holly EA; Hung RI; Janout V; Kurtz RC; Lee IM; Malats N; McKean D; Milne RL; Newton CC; Oberg AL; Perdomo S; Peters U; Porta M; Rothman N; Schulze MB; Sesso HD; Silverman DT; Thompson IM; Wactawski-Wende J; Weiderpass E; Wenstzensen N; White E; Wilkens LR; Yu H; Zeleniuch-Jacquotte A; Zhong J; Kraft P; Li D; Campbell PT; Petersen GM; Wolpin BM; Risch HA; Amundadottir LT; Klein AP; Yu K; Stolzenberg-Solomon RZ | October 4, 2021 | PubMed abstract

Weight loss or lower body mass index (BMI) could be an early symptom of Alzheimer disease (AD), but when this begins to emerge is difficult to estimate with traditional observational data. In an extension of Mendelian randomization, we leveraged variation in genetic risk for late-onset AD risk to estimate the causal effect of AD on BMI and the earliest ages at which AD-related weight loss (or lower BMI as a proxy) occurs. We studied UK Biobank participants enrolled in 2006-2010, who were without dementia, aged 39-73, with European genetic ancestry. BMI was calculated with measured height/weight (weight (kg)/height (m)2). An AD genetic risk score (AD-GRS) was calculated based on 23 genetic variants. Using linear regressions, we tested the association of AD-GRS with BMI, stratified by decade, and calculated the age of divergence in BMI trends between low and high AD-GRS. AD-GRS was not associated with BMI in 39- to 49-year-olds (β = 0.00, 95% confidence interval (CI): -0.03, 0.03). AD-GRS was associated with lower BMI in 50- to 59-year-olds (β = -0.03, 95% CI: -0.06, -0.01) and 60- to 73-year-olds (β = -0.09, 95% CI:-0.12, -0.07). Model-based BMI age curves for high versus low AD-GRS began to diverge after age 47 years. Sensitivity analyses found no evidence for pleiotropy or survival bias. Longitudinal replication is needed; however, our findings suggest that AD genes might begin to reduce BMI decades prior to dementia diagnosis.

Authors: Brenowitz, Willa D.; Zimmerman, Scott C.; Filshtein, Teresa J.; Yaffe, Kristine; Walter, Stefan; Hoffmann, Thomas J.; Jorgenson, Eric; Whitmer, Rachel A.; Glymour, M. Maria | October 1, 2021 | PubMed abstract

The question associated with efficacy and longevity of SARS-CoV-2 protection post-vaccination is paramount. The cPass surrogate virus neutralization test (sVNT) has gained popularity globally as a dual application assay for: 1. Accurate SARS-CoV-2 population surveillance (seroprevalence) analysis and 2. Revealing the presence of antibodies that block and effectively neutralize the interaction between the SARS-CoV-2 receptor binding domain and the host cell ACE2 receptor in recovered or vaccinated individuals. This study describes an approach for accurate quantification of neutralizing antibodies using the cPass sVNT with an automated workflow on the Tecan EVO and Dynex Agility platforms that is applicable to other liquid handling systems. This methodology was used to assess the stability of SARS-CoV-2 neutralizing antibodies between freeze/thaw and refrigerated sample storage conditions. Furthermore, a subset of twenty-five samples from SARS-CoV-2 infected/recovered individuals revealed a 600-fold difference in the neutralizing antibody response where low titers were represented in about half of the samples. Finally, pre- and post-vaccination samples were tested for neutralizing antibodies using the qualitative and semi-quantitative cPass sVNT protocols revealing undetectable or relatively low levels after the first vaccine dose and a decline in levels longitudinally over the months following the second dose. This wide range in neutralizing (blocking) antibodies from both natural infection and vaccination supports a differential immune response that may be attributed to several physiological and genetic factors underlining the potential for measuring SARS-CoV-2 neutralizing antibody titer levels post-vaccination to help ensure robust and prolonged immunity.

Authors: Taylor SC; Hurst B; Martiszus I; Hausman MS; Sarwat S; Schapiro JM; Rowell S; Lituev A | September 15, 2021 | PubMed abstract

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Authors: Jia X; Goes FS; Locke AE; Palmer D; Wang W; Cohen-Woods S; Genovese G; Jackson AU; Jiang C; Kvale M; Mullins N; Nguyen H; Pirooznia M; Rivera M; Ruderfer DM; Shen L; Thai K; Zawistowski M; Zhuang Y; Abecasis G; Akil H; Bergen S; Burmeister M; Chapman S; DelaBastide M; Juréus A; Kang HM; Kwok PY; Li JZ; Levy SE; Monson ET; Moran J; Sobell J; Watson S; Willour V; Zöllner S; Adolfsson R; Blackwood D; Boehnke M; Breen G; Corvin A; Craddock N; DiFlorio A; Hultman CM; Landen M; Lewis C; McCarroll SA; Richard McCombie W; McGuffin P; McIntosh A; McQuillin A; Morris D; Myers RM; O'Donovan M; Ophoff R; Boks M; Kahn R; Ouwehand W; Owen M; Pato C; Pato M; Posthuma D; Potash JB; Reif A; Sklar P; Smoller J; Sullivan PF; Vincent J; Walters J; Neale B; Purcell S; Risch N; Schaefer C; Stahl EA; Zandi PP; Scott LJ | September 1, 2021 | PubMed abstract

The association between the c.521T>C variant allele in SLCO1B1 (reference single nucleotide polymorphism (rs)4149056) and simvastatin-induced myotoxicity was discovered over a decade ago; however, whether this relationship represents a class effect is still not fully known. The aim of this study was to investigate the relationship between rs4149056 genotype and statin-induced myotoxicity in patients taking atorvastatin and lovastatin. Study participants were from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. A total of 233 statin-induced myopathy + rhabdomyolysis cases met the criteria for inclusion and were matched to 2,342 controls. To validate the drug response phenotype, we replicated the previously established association between rs4149056 genotype and simvastatin-induced myotoxicity. In particular, compared with homozygous T allele carriers, there was a significantly increased risk of simvastatin-induced myopathy + rhabdomyolysis in homozygous carriers of the C allele (CC vs. TT, odds ratio [OR] 4.62, 95% confidence interval [CI] 1.58-11.90, P = 0.003). For lovastatin users, homozygous carriers of the C allele were also at increased risk of statin-induced myopathy + rhabdomyolysis (CC vs. TT, OR 4.49, 95% CI 1.68-10.80, P = 0.001). In atorvastatin users, homozygous carriers of the C allele were twice as likely to experience statin-induced myopathy, though this association did not achieve statistical significance (CC vs. TT, OR 2.00, 95% CI 0.44-6.59, P = 0.30). In summary, our findings suggest that the association of rs4149056 with simvastatin-related myotoxicity may also extend to lovastatin. More data is needed to determine the extent of the association in atorvastatin users. Altogether, these data expand the evidence base for informing guidelines of pharmacogenetic-based statin prescribing practices.

Authors: Lu B; Sun L; Seraydarian M; Hoffmann TJ; Medina MW; Iribarren C; Krauss RM; Risch N; Oni-Orisan A | September 1, 2021 | PubMed abstract

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel-like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P = 4.73 × 10-6), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP.

Authors: Nair KS; Srivastava C; Brown RV; Koli S; Choquet H; Kang HS; Kuo YM; Grimm SA; Sutherland C; Badea A; Johnson GA; Zhao Y; Yin J; Okamoto K; Clark G; Borrás T; Zode G; Kizhatil K; Chakrabarti S; John SWM; Jorgenson E; Jetten AM | August 12, 2021 | PubMed abstract

This study aimed to screen the entire genome for genetic markers associated with risk for Achilles tendon injury. A genome-wide association analysis was performed using data from the Kaiser Permanente Research Board and the UK Biobank. Achilles tendon injury cases were identified based on electronic health records from the Kaiser Permanente Research Board databank and the UK Biobank from individuals of European ancestry. Genome-wide association analyses from both cohorts were tested for Achilles tendon injury using a logistic regression model adjusting for sex, height, weight, and race/ethnicity using allele counts for single nucleotide polymorphisms (SNP). Previously identified genes within the literature were also tested for association with Achilles tendon injury. There were a total of 12,354 cases of Achilles tendon injury and 483,080 controls within the two combined cohorts, with 67 SNP in three chromosomal loci demonstrating a genome-wide significant association with Achilles tendon injury. The first locus contains a single SNP (rs183364169) near the CDCP1 and TMEM158 genes on chromosome 3. The second locus contains 65 SNP in three independently segregating sets near the MPP7 gene on chromosome 10. The last locus contains a single SNP (rs4454832) near the SOX21 and GPR180 genes on chromosome 13. The current data were used to test 14 candidate genes previously reported to show an association with Achilles tendon injury, but none showed a significant association (all P > 0.05). Three loci were identified as potential risk factors for Achilles tendon injury and deserve further validation and investigation of molecular mechanisms.

Authors: Kim SK; Nguyen C; Avins AL; Abrams GD | August 1, 2021 | PubMed abstract

Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.

Authors: Choquet H; Yin J; Jacobson AS; Horton BH; Hoffmann TJ; Jorgenson E; Avins AL; Pressman AR | July 22, 2021 | PubMed abstract

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 OAS1 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of OAS1 . We suggest that genetically-regulated loss of OAS1 expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the OAS1 risk haplotypes.

Authors: Banday AR; Stanifer ML; Florez-Vargas O; Onabajo OO; Zahoor MA; Papenberg BW; Ring TJ; Lee CH; Andreakos E; Arons E; Barsh G; Biesecker LG; Boyle DL; Burnett-Hartman A; Carrington M; Chang E; Choe PG; Chrisholm RL; Dalgard C; Edberg J; Erdmann N; Feigelson HS; Firestein GS; Gehring AJ; Ho M; Holland S; Hutchinson AA; Im H; Ison MG; Kim HB; Kreitman RJ; Korf BR; Mirabello L; Pacheco JA; Peluso MJ; Rader DJ; Redden DT; Ritchie MD; Rosenbloom B; Sant Anna HP; Savage S; Siouti E; Triantafyllia V; Vargas JM; Verma A; Vij V; Wesemann DR; Yeager M; Yu X; Zhang Y; Boulant S; Chanock SJ; Feld JJ; Prokunina-Olsson L | July 13, 2021 | PubMed abstract

Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including n = 229 African American and n = 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, n = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (n = 27,955) and Hispanic/Latino (n = 28,324) ancestry participants. Our results revealed 24 suggestive signals (p < 1 × 10-4) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN. These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.

Authors: Wen J; Xie M; Rowland B; Rosen JD; Sun Q; Chen J; Tapia AL; Qian H; Kowalski MH; Shan Y; Young KL; Graff M; Argos M; Avery CL; Bien SA; Buyske S; Yin J; Choquet H; Fornage M; Hodonsky CJ; Jorgenson E; Kooperberg C; Loos RJF; Liu Y; Moon JY; North KE; Rich SS; Rotter JI; Smith JA; Zhao W; Shang L; Wang T; Zhou X; Reiner AP; Raffield LM; Li Y | July 8, 2021 | PubMed abstract

Prior work proposed a shortened version of the Social Responsiveness Scale (SRS), a commonly used quantitative measure of social communication traits. We used data from 3031 participants (including 190 ASD cases) from the Environmental Influences on Child Health Outcomes (ECHO) Program to compare distributional properties and criterion validity of 16-item “short” to 65-item “full” SRS scores. Results demonstrated highly overlapping distributions of short and full scores. Both scores separated case from non-case individuals by approximately two standard deviations. ASD prediction was nearly identical for short and full scores (area under the curve values of 0.87, 0.86 respectively). Findings support comparability of shortened and full scores, suggesting opportunities to increase efficiency. Future work should confirm additional psychometric properties of short scores.

Authors: Lyall K; Hosseini M; Ladd-Acosta C; Ning X; Catellier D; Constantino JN; Croen LA; Kaat AJ; Botteron K; Bush NR; Dager SR; Duarte CS; Fallin MD; Hazlett H; Hertz-Picciotto I; Joseph RM; Karagas MR; Korrick S; Landa R; Messinger D; Oken E; Ozonoff S; Piven J; Pandey J; Sathyanarayana S; Schultz RT; St John T; Schmidt R; Volk H; Newschaffer CJ; program collaborators for Environmental influences on Child Health Outcomes | July 1, 2021 | PubMed abstract

Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex human diseases from the Electronic Medical Records and Genomics (347 traits) and the UK Biobank (549 traits). Aside from 67 new lipid-associated genes with strong replication, we found evidence for pleiotropic SNPs/genes between lipids and diseases across the phenome. These include discordant pleiotropy in the HLA region between lipids and multiple sclerosis and putative causal paths between triglycerides and gout, among several others. Our findings give insights into the genetic basis of the relationship between plasma lipids and diseases on a phenome-wide scale and can provide context for future prevention and treatment strategies.

Authors: Veturi, Yogasudha; Lucas, Anastasia; Bradford, Yuki; Hui, Daniel; Dudek, Scott; Theusch, Elizabeth; Verma, Anurag; Miller, Jason E.; Kullo, Iftikhar; Hakonarson, Hakon; Sleiman, Patrick; Schaid, Daniel; Stein, Charles M.; Edwards, Digna R. Velez; Feng, QiPing; Wei, Wei-Qi; Medina, Marisa W.; Krauss, Ronald M.; Hoffmann, Thomas J.; Risch, Neil; Voight, Benjamin F.; Rader, Daniel J.; Ritchie, Marylyn D. | July 1, 2021 | PubMed abstract

Cataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States. As the genetic etiology of cataract formation remains unclear, we conducted a multiethnic genome-wide association meta-analysis, combining results from the GERA and UK Biobank cohorts, and tested for replication in the 23andMe research cohort. We report 54 genome-wide significant loci, 37 of which were novel. Sex-stratified analyses identified CASP7 as an additional novel locus specific to women. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages as per iSyTE analysis. Furthermore, iSyTE shows 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology. Our work provides further insight into the complex genetic architecture of cataract susceptibility.

Authors: Choquet H; Melles RB; Anand D; Yin J; Cuellar-Partida G; Wang W; 23andMe Research Team; Hoffmann TJ; Nair KS; Hysi PG; Lachke SA; Jorgenson E | June 14, 2021 | PubMed abstract

The aim of this study was to screen the entire genome for genetic markers associated with risk for anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) injury. Genome-wide association (GWA) analyses were performed using data from the Kaiser Permanente Research Board (KPRB) and the UK Biobank. ACL and PCL injury cases were identified based on electronic health records from KPRB and the UK Biobank. GWA analyses from both cohorts were tested for ACL and PCL injury using a logistic regression model adjusting for sex, height, weight, age at enrolment, and race/ethnicity using allele counts for single nucleotide polymorphisms (SNPs). The data from the two GWA studies were combined in a meta-analysis. Candidate genes previously reported to show an association with ACL injury in athletes were also tested for association from the meta-analysis data from the KPRB and the UK Biobank GWA studies. There was a total of 2,214 cases of ACL and PCL injury and 519,869 controls within the two cohorts, with three loci demonstrating a genome-wide significant association in the meta-analysis: INHBA, AEBP2, and LOC101927869. Of the eight candidate genes previously studied in the literature, six were present in the current dataset, and only COL3A1 (rs1800255) showed a significant association (p = 0.006). Genetic markers in three novel loci in this study and one previously-studied candidate gene were identified as potential risk factors for ACL and PCL injury and deserve further validation and investigation of molecular mechanisms. Cite this article: Bone Jt Open 2021;2(6):414-421.

Authors: Kim SK; Nguyen C; Avins AL; Abrams GD | June 1, 2021 | PubMed abstract

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P interaction = 3.08 × 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r 2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

Authors: Mocci E; Kundu P; Wheeler W; Arslan AA; Beane-Freeman LE; Bracci PM; Brennan P; Canzian F; Du M; Gallinger S; Giles GG; Goodman PJ; Kooperberg C; Le Marchand L; Neale RE; Shu XO; Visvanathan K; White E; Zheng W; Albanes D; Andreotti G; Babic A; Bamlet WR; Berndt SI; Blackford AL; Bueno-de-Mesquita B; Buring JE; Campa D; Chanock SJ; Childs EJ; Duell EJ; Fuchs CS; Gaziano JM; Giovannucci EL; Goggins MG; Hartge P; Hassan MM; Holly EA; Hoover RN; Hung RJ; Kurtz RC; Lee IM; Malats N; Milne RL; Ng K; Oberg AL; Panico S; Peters U; Porta M; Rabe KG; Riboli E; Rothman N; Scelo G; Sesso HD; Silverman DT; Stevens VL; Strobel O; Thompson IM; Tjonneland A; Trichopoulou A; Van Den Eeden SK; Wactawski-Wende J; Wentzensen N; Wilkens LR; Yu H; Yuan F; Zeleniuch-Jacquotte A; Amundadottir LT; Li D; Jacobs EJ; Petersen GM; Wolpin BM; Risch HA; Kraft P; Chatterjee N; Klein AP; Stolzenberg-Solomon R | June 1, 2021 | PubMed abstract

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

Authors: Hu Y; Stilp AM; McHugh CP; Rao S; Jain D; Zheng X; Lane J; Méric de Bellefon S; Raffield LM; Chen MH; Yanek LR; Wheeler M; Yao Y; Ren C; Broome J; Moon JY; de Vries PS; Hobbs BD; Sun Q; Surendran P; Brody JA; Blackwell TW; Choquet H; Ryan K; Duggirala R; Heard-Costa N; Wang Z; Chami N; Preuss MH; Min N; Ekunwe L; Lange LA; Cushman M; Faraday N; Curran JE; Almasy L; Kundu K; Smith AV; Gabriel S; Rotter JI; Fornage M; Lloyd-Jones DM; Vasan RS; Smith NL; North KE; Boerwinkle E; Becker LC; Lewis JP; Abecasis GR; Hou L; O'Connell JR; Morrison AC; Beaty TH; Kaplan R; Correa A; Blangero J; Jorgenson E; Psaty BM; Kooperberg C; Walton RT; Kleinstiver BP; Tang H; Loos RJF; Soranzo N; Butterworth AS; Nickerson D; Rich SS; Mitchell BD; Johnson AD; Auer PL; Li Y; Mathias RA; Lettre G; Pankratz N; Laurie CC; Laurie CA; Bauer DE; Conomos MP; Reiner AP; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium | May 6, 2021 | PubMed abstract

Air pollution exposure is ubiquitous with demonstrated effects on morbidity and mortality. A growing literature suggests that prenatal air pollution exposure impacts neurodevelopment. We posit that the Environmental influences on Child Health Outcomes (ECHO) program will provide unique opportunities to fill critical knowledge gaps given the wide spatial and temporal variability of ECHO participants. We briefly describe current methods for air pollution exposure assessment, summarize existing studies of air pollution and neurodevelopment, and synthesize this information as a basis for recommendations, or a blueprint, for evaluating air pollution effects on neurodevelopmental outcomes in ECHO. We review peer-reviewed literature on prenatal air pollution exposure and neurodevelopmental outcomes, including autism spectrum disorder, attention deficit hyperactivity disorder, intelligence, general cognition, mood, and imaging measures. ECHO meta-data were compiled and evaluated to assess frequency of neurodevelopmental assessments and prenatal and infancy residential address locations. Cohort recruitment locations and enrollment years were summarized to examine potential spatial and temporal variation present in ECHO. While the literature provides compelling evidence that prenatal air pollution affects neurodevelopment, limitations in spatial and temporal exposure variation exist for current published studies. As >90% of the ECHO cohorts have collected a prenatal or infancy address, application of advanced geographic information systems-based models for common air pollutant exposures may be ideal to address limitations of published research. In ECHO we have the opportunity to pioneer unifying exposure assessment and evaluate effects across multiple periods of development and neurodevelopmental outcomes, setting the standard for evaluation of prenatal air pollution exposures with the goal of improving children’s health.

Authors: Volk HE; Perera F; Braun JM; Kingsley SL; Gray K; Buckley J; Clougherty JE; Croen LA; Eskenazi B; Herting M; Just AC; Kloog I; Margolis A; McClure LA; Miller R; Levine S; Wright R; Environmental influences on Child Health Outcomes | May 1, 2021 | PubMed abstract

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

Authors: Currant H; Hysi P; Fitzgerald TW; Gharahkhani P; Bonnemaijer PWM; Senabouth A; Hewitt AW; UK Biobank Eye and Vision Consortium; International Glaucoma Genetics Consortium; Atan D; Aung T; Charng J; Choquet H; Craig J; Khaw PT; Klaver CCW; Kubo M; Ong JS; Pasquale LR; Reisman CA; Daniszewski M; Powell JE; Pébay A; Simcoe MJ; Thiadens AAHJ; van Duijn CM; Yazar S; Jorgenson E; MacGregor S; Hammond CJ; Mackey DA; Wiggs JL; Foster PJ; Patel PJ; Birney E; Khawaja AP | May 1, 2021 | PubMed abstract

Adoption of prognostic molecular assays for prostate cancer requires evidence of robust performance in different racial groups. Retrospective analysis was conducted to assess the performance of the Oncotype DX® Genomic Prostate Score® test in African American and Caucasian American men with surgically treated prostate cancer. We compared the assay results (scale 0-100) and the 4 gene group scores in biopsy specimens from 201 African American and 1,144 Caucasian American men with clinically localized prostate cancer in 6 cohorts. Adverse pathology was defined as high grade (primary Gleason pattern 4 or any pattern 5) and/or nonorgan-confined disease (≥pT3). Binary logistic regression models were used for adverse pathology. Biochemical recurrence was defined as 2 successive prostate specific antigen levels >0.2 ng/ml or initiation of salvage therapy after radical prostatectomy. Cox proportional hazards models evaluated the association of the assay result or racial group with time to biochemical recurrence. Each cohort had different clinical risk distributions and percentages of African Americans, although median and interquartile ranges of the assay results and gene group scores were similar between both racial groups. In a multivariable model with the assay and pathological/clinical features including race, the assay was significantly associated with adverse pathology (p ≤0.004) and biochemical recurrence (p <0.001). Race was not a significant predictor of either end point. The assay is similarly predictive of outcomes in African American and Caucasian American patients, and improves risk stratification in men with newly diagnosed prostate cancer from both racial groups.

Authors: Cullen J; Lynch JA; Klein EA; Van Den Eeden SK; Carroll PR; Mohler JL; Knezevic D; Farrington TA; Lu R | April 1, 2021 | PubMed abstract

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, P = 2.55 × 10-191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.See related commentary by Lachance, p. 1637.

Authors: Emami NC; Cavazos TB; Rashkin SR; Graff RE; Tai CG; Mefford JA; Kachuri L; Cario CL; Wan E; Wong S; Aaronson D; Presti J; Habel LA; Shan J; Ranatunga DK; Chao CR; Ghai NR; Jorgenson E; Sakoda LC; Kvale MN; Kwok PY; Schaefer C; Risch N; Hoffmann TJ; Van Den Eeden SK; Witte JS | April 1, 2021 | PubMed abstract

This study aimed to screen the entire genome for genetic markers associated with risk for concussion. A genome-wide association analyses was performed using data from the Kaiser Permanente Research Bank and the UK Biobank. Concussion cases were identified based on electronic health records from the Kaiser Permanente Research Bank and the UK Biobank from individuals of European ancestry. Genome-wide association analyses from both cohorts were tested for concussion using a logistic regression model adjusting for sex, height, weight, and race/ethnicity using allele counts for single nucleotide polymorphisms. Previously identified genes within the literature were also tested for association with concussion. There were a total of 4064 cases of concussion and 291,472 controls within the databases, with two single nucleotide polymorphisms demonstrating a genome-wide significant association with concussion. The first polymorphism, rs144663795 (P = 9.7 × 10-11; OR = 2.91 per allele copy), is located within the intron of SPATA5. Strong, deleterious mutations in SPATA5 cause intellectual disability, hearing loss, and vision loss. The second polymorphism, rs117985931 (P = 3.97 × 10-9; OR = 3.59 per allele copy), is located within PLXNA4. PLXNA4 plays a key role is axon outgrowth during neural development, and DNA variants in PLXNA4 are associated with risk for Alzheimer’s disease. Previous investigations have identified five candidate genes that may be associated with concussion, but none showed a significant association in the current model (P < 0.05). Two genetic markers were identified as potential risk factors for concussion and deserve further validation and investigation of molecular mechanisms.

Authors: Kim SK; Roche MD; Fredericson M; Dragoo JL; Horton BH; Avins AL; Belanger HG; Ioannidis JPA; Abrams GD | April 1, 2021 | PubMed abstract

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

Authors: Andlauer, Till F. M.; Guzman-Parra, Jose; Streit, Fabian; Strohmaier, Jana; González, Maria José; Gil Flores, Susana; Cabaleiro Fabeiro, Francisco J.; Del Río Noriega, Francisco; Perez, Fermin Perez; Haro González, Jesus; Orozco Diaz, Guillermo; de Diego-Otero, Yolanda; Moreno-Küstner, Berta; Auburger, Georg; Degenhardt, Franziska; Heilmann-Heimbach, Stefanie; Herms, Stefan; Hoffmann, Per; Frank, Josef; Foo, Jerome C.; Treutlein, Jens; Witt, Stephanie H.; Cichon, Sven; Kogevinas, Manolis; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Rivas, Fabio; Mayoral, Fermín; Müller-Myhsok, Bertram; Forstner, Andreas J.; Nöthen, Markus M.; Rietschel, Marcella | April 1, 2021 | PubMed abstract

Genome-wide association meta-analysis (GWAMA) is an effective approach to enlarge sample sizes and empower the discovery of novel associations between genotype and phenotype. Independent replication has been used as a gold-standard for validating genetic associations. However, as current GWAMA often seeks to aggregate all available datasets, it becomes impossible to find a large enough independent dataset to replicate new discoveries. Here we introduce a method, MAMBA (Meta-Analysis Model-based Assessment of replicability), for assessing the “posterior-probability-of-replicability” for identified associations by leveraging the strength and consistency of association signals between contributing studies. We demonstrate using simulations that MAMBA is more powerful and robust than existing methods, and produces more accurate genetic effects estimates. We apply MAMBA to a large-scale meta-analysis of addiction phenotypes with 1.2 million individuals. In addition to accurately identifying replicable common variant associations, MAMBA also pinpoints novel replicable rare variant associations from imputation-based GWAMA and hence greatly expands the set of analyzable variants.

Authors: McGuire, Daniel; Jiang, Yu; Liu, Mengzhen; Weissenkampen, J. Dylan; Eckert, Scott; Yang, Lina; Chen, Fang; GWAS and Sequencing Consortium of Alcohol and Nicotine Use (GSCAN); Berg, Arthur; Vrieze, Scott; Jiang, Bibo; Li, Qunhua; Liu, Dajiang J. | March 30, 2021 | PubMed abstract

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Authors: Hardcastle AJ; Liskova P; Bykhovskaya Y; McComish BJ; Davidson AE; Inglehearn CF; Li X; Choquet H; Habeeb M; Lucas SEM; Sahebjada S; Pontikos N; Lopez KER; Khawaja AP; Ali M; Dudakova L; Skalicka P; Van Dooren BTH; Geerards AJM; Haudum CW; Faro VL; Tenen A; Simcoe MJ; Patasova K; Yarrand D; Yin J; Siddiqui S; Rice A; Farraj LA; Chen YI; Rahi JS; Krauss RM; Theusch E; Charlesworth JC; Szczotka-Flynn L; Toomes C; Meester-Smoor MA; Richardson AJ; Mitchell PA; Taylor KD; Melles RB; Aldave AJ; Mills RA; Cao K; Chan E; Daniell MD; Wang JJ; Rotter JI; Hewitt AW; MacGregor S; Klaver CCW; Ramdas WD; Craig JE; Iyengar SK; O'Brart D; Jorgenson E; Baird PN; Rabinowitz YS; Burdon KP; Hammond CJ; Tuft SJ; Hysi PG | March 1, 2021 | PubMed abstract

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Authors: Gharahkhani P; Jorgenson E; Hysi P; Khawaja AP; Pendergrass S; Han X; Ong JS; Hewitt AW; Segrè AV; Rouhana JM; Hamel AR; Igo RP; Choquet H; Qassim A; Josyula NS; Cooke Bailey JN; Bonnemaijer PWM; Iglesias A; Siggs OM; Young TL; Vitart V; Thiadens AAHJ; Karjalainen J; Uebe S; Melles RB; Nair KS; Luben R; Simcoe M; Amersinghe N; Cree AJ; Hohn R; Poplawski A; Chen LJ; Rong SS; Aung T; Vithana EN; NEIGHBORHOOD consortium; ANZRAG consortium; Biobank Japan project; FinnGen study; UK Biobank Eye and Vision Consortium; GIGA study group; 23 and Me Research Team; Tamiya G; Shiga Y; Yamamoto M; Nakazawa T; Currant H; Birney E; Wang X; Auton A; Lupton MK; Martin NG; Ashaye A; Olawoye O; Williams SE; Akafo S; Ramsay M; Hashimoto K; Kamatani Y; Akiyama M; Momozawa Y; Foster PJ; Khaw PT; Morgan JE; Strouthidis NG; Kraft P; Kang JH; Pang CP; Pasutto F; Mitchell P; Lotery AJ; Palotie A; van Duijn C; Haines JL; Hammond C; Pasquale LR; Klaver CCW; Hauser M; Khor CC; Mackey DA; Kubo M; Cheng CY; Craig JE; MacGregor S; Wiggs JL | February 24, 2021 | PubMed abstract

Despite increasing regulation, exposure to persistent organic pollutants (POPs) remains a serious public health concern due to their accumulation in the environment and ability to biomagnify up the food chain. POPs are associated with endocrine-disrupting effects including adverse reproductive outcomes that could affect fecundability, i.e. the capacity to conceive a pregnancy, quantified as time to pregnancy (TTP). Results of epidemiologic studies that examine the impact of various chemical classes of POPs on TTP have not been synthesised. We undertook a systematic review to summarise the strength of evidence for associations of four common groups of POPs with couple fecundability and to identify gaps and limitations in the literature in order to inform policy decisions and future research. We performed an electronic search of literature published between 1 January 2007 and 6 August 2019 in MEDLINE, EMBASE.com, Global Health, DART/TOXLINE and POPLINE. We included empirical research papers that examined human exposure to organochlorine (OC) pesticides, brominated flame retardants, polychlorinated organic compounds and/or per- and polyfluoroalkyl substances (PFAS) and considered TTP or fecundability as an outcome. Standardised forms for screening, data extraction and study quality were developed using DistillerSR software, and all reviews were completed in duplicate. We used the Newcastle-Ottawa Scale to assess risk of bias and devised additional quality metrics based on specific methodological features of fecundability studies. The search returned 4573 articles, and 28 papers from 19 different studies met inclusion criteria. Among them, four studies measured TTP prospectively, three had data on participants’ prenatal exposure, three examined associations in both male and female partners and one focused exclusively on males. Analyses varied widely in terms of exposure characterisation, precluding a meta-analytic approach. Evidence was strongest for adverse associations of female exposure to polychlorinated biphenyls with TTP, with some additional support for associations of female exposure to polybrominated diphenyl ethers and PFAS with longer TTP. Our review provided little or no support for associations between female exposure to OC pesticides or male exposure to any of the POP groups and TTP. Evidence suggests that female exposure to at least some POPs may reduce fecundability. Although many of these chemicals are no longer in production, they are still detectable in human biosamples because of their persistence in the environment. Replacement chemicals that are being introduced as older ones are restricted may have similar reproductive consequences. Future studies should examine these newer POPs, assess interactions between POPs and other chemical and non-chemical exposures, investigate how POPs are distributed in and metabolised by the human body and focus on populations that may be disproportionately exposed.

Authors: Kahn LG; Harley KG; Siegel EL; Zhu Y; Factor-Litvak P; Porucznik CA; Klein-Fedyshin M; Hipwell AE; program collaborators for Environmental Influences on Child Health Outcomes Program | February 19, 2021 | PubMed abstract

Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.

Authors: Graff RE; Cavazos TB; Thai KK; Kachuri L; Rashkin SR; Hoffman JD; Alexeeff SE; Blatchins M; Meyers TJ; Leong L; Tai CG; Emami NC; Corley DA; Kushi LH; Ziv E; Van Den Eeden SK; Jorgenson E; Hoffmann TJ; Habel LA; Witte JS; Sakoda LC | February 12, 2021 | PubMed abstract

Cigarette smoking contributes to numerous diseases and is one of the leading causes of death in the United States. Smoking behaviors vary widely across race/ethnicity, but it is not clear why. Here, we examine the contribution of genetic ancestry to variation in two smoking-related traits in 43,485 individuals from four race/ethnicity groups (non-Hispanic white, Hispanic/Latino, East Asian, and African American) from a single U.S. healthcare plan. Smoking prevalence was the lowest among East Asians (22.7%) and the highest among non-Hispanic whites (38.5%). We observed significant associations between genetic ancestry and smoking-related traits. Within East Asians, we observed higher smoking prevalence with greater European (versus Asian) ancestry (P = 9.95 × 10-12). Within Hispanic/Latinos, higher cigarettes per day (CPD) was associated with greater European ancestry (P = 3.34 × 10-25). Within non-Hispanic whites, the lowest number of CPD was observed for individuals of southeastern European ancestry (P = 9.06 × 10-5). These associations remained after considering known smoking-associated loci, education, socioeconomic factors, and marital status. Our findings support the role of genetic ancestry and socioeconomic factors in cigarette smoking behaviors in non-Hispanic whites, Hispanic/Latinos, and East Asians.

Authors: Choquet H; Yin J; Jorgenson E | February 11, 2021 | PubMed abstract

Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10-17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10-24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10-10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10-10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10-8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes. These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.

Authors: Campbell PT; Lin Y; Bien SA; Figueiredo JC; Harrison TA; Guinter MA; Berndt SI; Brenner H; Chan AT; Chang-Claude J; Gallinger SJ; Gapstur SM; Giles GG; Giovannucci E; Gruber SB; Gunter M; Hoffmeister M; Jacobs EJ; Jenkins MA; Le Marchand L; Li L; McLaughlin JR; Murphy N; Milne RL; Newcomb PA; Newton C; Ogino S; Potter JD; Rennert G; Rennert HS; Robinson J; Sakoda LC; Slattery ML; Song Y; White E; Woods MO; Casey G; Hsu L; Peters U | January 4, 2021 | PubMed abstract

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Authors: Conti DV; Darst BF; Moss LC; Saunders EJ; Sheng X; Chou A; Schumacher FR; Olama AAA; Benlloch S; Dadaev T; Brook MN; Sahimi A; Hoffmann TJ; Takahashi A; Matsuda K; Momozawa Y; Fujita M; Muir K; Lophatananon A; Wan P; Le Marchand L; Wilkens LR; Stevens VL; Gapstur SM; Carter BD; Schleutker J; Tammela TLJ; Sipeky C; Auvinen A; Giles GG; Southey MC; MacInnis RJ; Cybulski C; Wokołorczyk D; Lubiński J; Neal DE; Donovan JL; Hamdy FC; Martin RM; Nordestgaard BG; Nielsen SF; Weischer M; Bojesen SE; Røder MA; Iversen P; Batra J; Chambers S; Moya L; Horvath L; Clements JA; Tilley W; Risbridger GP; Gronberg H; Aly M; Szulkin R; Eklund M; Nordström T; Pashayan N; Dunning AM; Ghoussaini M; Travis RC; Key TJ; Riboli E; Park JY; Sellers TA; Lin HY; Albanes D; Weinstein SJ; Mucci LA; Giovannucci E; Lindstrom S; Kraft P; Hunter DJ; Penney KL; Turman C; Tangen CM; Goodman PJ; Thompson IM; Hamilton RJ; Fleshner NE; Finelli A; Parent MÉ; Stanford JL; Ostrander EA; Geybels MS; Koutros S; Freeman LEB; Stampfer M; Wolk A; Håkansson N; Andriole GL; Hoover RN; Machiela MJ; Sørensen KD; Borre M; Blot WJ; Zheng W; Yeboah ED; Mensah JE; Lu YJ; Zhang HW; Feng N; Mao X; Wu Y; Zhao SC; Sun Z; Thibodeau SN; McDonnell SK; Schaid DJ; West CML; Burnet N; Barnett G; Maier C; Schnoeller T; Luedeke M; Kibel AS; Drake BF; Cussenot O; Cancel-Tassin G; Menegaux F; Truong T; Koudou YA; John EM; Grindedal EM; Maehle L; Khaw KT; Ingles SA; Stern MC; Vega A; Gómez-Caamaño A; Fachal L; Rosenstein BS; Kerns SL; Ostrer H; Teixeira MR; Paulo P; Brandão A; Watya S; Lubwama A; Bensen JT; Fontham ETH; Mohler J; Taylor JA; Kogevinas M; Llorca J; Castaño-Vinyals G; Cannon-Albright L; Teerlink CC; Huff CD; Strom SS; Multigner L; Blanchet P; Brureau L; Kaneva R; Slavov C; Mitev V; Leach RJ; Weaver B; Brenner H; Cuk K; Holleczek B; Saum KU; Klein EA; Hsing AW; Kittles RA; Murphy AB; Logothetis CJ; Kim J; Neuhausen SL; Steele L; Ding YC; Isaacs WB; Nemesure B; Hennis AJM; Carpten J; Pandha H; Michael A; De Ruyck K; De Meerleer G; Ost P; Xu J; Razack A; Lim J; Teo SH; Newcomb LF; Lin DW; Fowke JH; Neslund-Dudas C; Rybicki BA; Gamulin M; Lessel D; Kulis T; Usmani N; Singhal S; Parliament M; Claessens F; Joniau S; Van den Broeck T; Gago-Dominguez M; Castelao JE; Martinez ME; Larkin S; Townsend PA; Aukim-Hastie C; Bush WS; Aldrich MC; Crawford DC; Srivastava S; Cullen JC; Petrovics G; Casey G; Roobol MJ; Jenster G; van Schaik RHN; Hu JJ; Sanderson M; Varma R; McKean-Cowdin R; Torres M; Mancuso N; Berndt SI; Van Den Eeden SK; Easton DF; Chanock SJ; Cook MB; Wiklund F; Nakagawa H; Witte JS; Eeles RA; Kote-Jarai Z; Haiman CA | January 1, 2021 | PubMed abstract

Preterm birth occurs at excessively high and disparate rates in the United States. In 2016, the National Institutes of Health (NIH) launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate the influence of early life exposures on child health. Extant data from the ECHO cohorts provides the opportunity to examine racial and geographic variation in effects of individual- and neighborhood-level markers of socioeconomic status (SES) on gestational age at birth. The objective of this study was to examine the association between individual-level (maternal education) and neighborhood-level markers of SES and gestational age at birth, stratifying by maternal race/ethnicity, and whether any such associations are modified by US geographic region. Twenty-six ECHO cohorts representing 25,526 mother-infant pairs contributed to this disseminated meta-analysis that investigated the effect of maternal prenatal level of education (high school diploma, GED, or less; some college, associate’s degree, vocational or technical training [reference category]; bachelor’s degree, graduate school, or professional degree) and neighborhood-level markers of SES (census tract [CT] urbanicity, percentage of black population in CT, percentage of population below the federal poverty level in CT) on gestational age at birth (categorized as preterm, early term, full term [the reference category], late, and post term) according to maternal race/ethnicity and US region. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Cohort-specific results were meta-analyzed using a random effects model. For women overall, a bachelor’s degree or above, compared with some college, was associated with a significantly decreased odds of preterm birth (aOR 0.72; 95% CI: 0.61-0.86), whereas a high school education or less was associated with an increased odds of early term birth (aOR 1.10, 95% CI: 1.00-1.21). When stratifying by maternal race/ethnicity, there were no significant associations between maternal education and gestational age at birth among women of racial/ethnic groups other than non-Hispanic white. Among non-Hispanic white women, a bachelor’s degree or above was likewise associated with a significantly decreased odds of preterm birth (aOR 0.74 (95% CI: 0.58, 0.94) as well as a decreased odds of early term birth (aOR 0.84 (95% CI: 0.74, 0.95). The association between maternal education and gestational age at birth varied according to US region, with higher levels of maternal education associated with a significantly decreased odds of preterm birth in the Midwest and South but not in the Northeast and West. Non-Hispanic white women residing in rural compared to urban CTs had an increased odds of preterm birth; the ability to detect associations between neighborhood-level measures of SES and gestational age for other race/ethnic groups was limited due to small sample sizes within select strata. Interventions that promote higher educational attainment among women of reproductive age could contribute to a reduction in preterm birth, particularly in the US South and Midwest. Further individual-level analyses engaging a diverse set of cohorts are needed to disentangle the complex interrelationships among maternal education, neighborhood-level factors, exposures across the life course, and gestational age at birth outcomes by maternal race/ethnicity and US geography.

Authors: Dunlop AL; Essalmi AG; Alvalos L; Breton C; Camargo CA; Cowell WJ; Dabelea D; Dager SR; Duarte C; Elliott A; Fichorova R; Gern J; Hedderson MM; Thepaksorn EH; Huddleston K; Karagas MR; Kleinman K; Leve L; Li X; Li Y; Litonjua A; Ludena-Rodriguez Y; Madan JC; Nino JM; McEvoy C; O'Connor TG; Padula AM; Paneth N; Perera F; Sathyanarayana S; Schmidt RJ; Schultz RT; Snowden J; Stanford JB; Trasande L; Volk HE; Wheaton W; Wright RJ; McGrath M; program collaborators for Environmental Influences on Child Health Outcomes | January 1, 2021 | PubMed abstract

Killer cell immunoglobulin-like receptors (KIR) regulate immune responses in NK and CD8+ T cells via interaction with HLA ligands. KIR genes, including KIR2DS1, KIR3DL1, and KIR3DS1 have previously been implicated in psoriasis susceptibility. However, these previous studies were constrained to small sample sizes, in part due to the time and expense required for direct genotyping of KIR genes. Here, we implemented KIR*IMP to impute KIR copy number from single-nucleotide polymorphisms (SNPs) on chromosome 19 in the discovery cohort (n=11,912) from the PAGE consortium, University of California San Francisco, and the University of Dundee, and in a replication cohort (n=66,357) from Kaiser Permanente Northern California. Stratified multivariate logistic regression that accounted for patient ancestry and high-risk HLA alleles revealed that KIR2DL2 copy number was significantly associated with psoriasis in the discovery cohort (p ≤ 0.05). The KIR2DL2 copy number association was replicated in the Kaiser Permanente replication cohort. This is the first reported association of KIR2DL2 copy number with psoriasis and highlights the importance of KIR genetics in the pathogenesis of psoriasis.

Authors: Ahn R; Vukcevic D; Motyer A; Nititham J; Squire DM; Hollenbach JA; Norman PJ; Ellinghaus E; Nair RP; Tsoi LC; Oksenberg J; Foerster J; Lieb W; Weidinger S; Franke A; Elder JT; Jorgenson E; Leslie S; Liao W | January 1, 2021 | PubMed abstract

This study characterizes the mental health of Asian American older adults (aged 60+) who identify as sexual minorities (SM or lesbian, gay, bisexual) and compare to their non-Asian American and non-SM counterparts. Data were from the Research Program on Genes, Environment and Health (Aged 60+; N=185,478), a representative sample of healthcare members from Northern California. It includes SM (N=447) and heterosexual/non-SM (N=15,772) older adults who identify as Asian American (Chinese, Japanese, Filipino, and South Asian) and non-Asian American SM (N=3,890). Rates of dementia, anxiety, and PTSD were similar for both SM and non-SM Asian Americans. However, older lesbian and gay Asian Americans were more likely to have a depression diagnosis (30% vs. 18%, p=0.002) compared to non-SM. Overall, mental health outcomes were lower for Asian American SM compared to non-Asian American SM. We discuss need for understanding protective factors for mental health and implications for future interventions.

Authors: Flatt, Jason; Whitmer, Rachel; Gilsanz, Paola | December 16, 2020 | PubMed abstract

Over 3 million or more adults aged 60 + live in the US who identify as lesbian, gay, bisexual, transgender, and/or queer (LGBTQ). Less is known about dementia risk in LGBTQ older adults. We will discuss dementia risk and related risk factors among LGBTQ adults from multiple population-based and cohort studies. We found higher rates of subjective memory problems among lesbian, bisexual and transgender adults compared to both gay men and heterosexual men and women. Using medical record data, 8% (343) of LGB adults aged 60+ were diagnosed with dementia. They were more likely to identify as male (63% vs. 44%), had a higher education level (college degree+ 63% vs. 40%) and were younger than their non-LGB counterparts. These findings highlight dementia risk and related problems among LGBTQ older adults. Future studies are needed to better understand dementia risk and recruiting, screening and improving dementia-related outcomes in LGBTQ older adults.

Authors: Flatt, Jason | December 16, 2020 | PubMed abstract

Although cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in individuals of European ancestry, the incidence of cSCC in Hispanic/Latinos is also increasing. cSCC has both a genetic and environmental etiology. Here, we examine the role of genetic ancestry, skin pigmentation, and sun exposure in Hispanic/Latinos and non-Hispanic whites on cSCC risk. We observe an increased cSCC risk with greater European ancestry (P = 1.27 × 10-42) within Hispanic/Latinos and with greater northern (P = 2.38 × 10-65) and western (P = 2.28 × 10-49) European ancestry within non-Hispanic whites. These associations are significantly, but not completely, attenuated after considering skin pigmentation-associated loci, history of actinic keratosis, and sun-protected versus sun-exposed anatomical sites. We also report an association of the well-known pigment variant Ala111Thr (rs1426654) at SLC24A5 with cSCC in Hispanic/Latinos. These findings demonstrate a strong correlation of northwestern European genetic ancestry with cSCC risk in both Hispanic/Latinos and non-Hispanic whites, largely but not entirely mediated through its impact on skin pigmentation.

Authors: Jorgenson E; Choquet H; Yin J; Hoffmann TJ; Banda Y; Kvale MN; Risch N; Schaefer C; Asgari MM | December 14, 2020 | PubMed abstract

To use the case-only gene-environment (G [Formula: see text] E) interaction study design to estimate interaction between pregnancy before onset of MS symptoms and established genetic risk factors for MS among White adult females. We studied 2,497 female MS cases from 4 cohorts in the United States, Sweden, and Norway with clinical, reproductive, and genetic data. Pregnancy exposure was defined in 2 ways: (1) [Formula: see text] live birth pregnancy before onset of MS symptoms and (2) parity before onset of MS symptoms. We estimated interaction between pregnancy exposure and established genetic risk variants, including a weighted genetic risk score and both HLA and non-HLA variants, using logistic regression and proportional odds regression within each cohort. Within-cohort associations were combined using inverse variance meta-analyses with random effects. The case-only G × E independence assumption was tested in 7,067 individuals without MS. Evidence for interaction between pregnancy exposure and established genetic risk variants, including the strongly associated HLA-DRB1*15:01 allele and a weighted genetic risk score, was not observed. Results from sensitivity analyses were consistent with observed results. Our findings indicate that pregnancy before symptom onset does not modify the risk of MS in genetically susceptible White females.

Authors: Adams CJ; Wu SL; Shao X; Bradshaw PT; Gonzales E; Smith JB; Xiang AH; Bellesis KH; Chinn T; Bos SD; Wendel-Haga M; Olsson T; Kockum I; Langer-Gould AM; Schaefer C; Alfredsson L; Barcellos LF | November 1, 2020 | PubMed abstract

Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10-8, tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P < 0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk (P < 0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk.

Authors: Sieh W; Rothstein JH; Klein RJ; Alexeeff SE; Sakoda LC; Jorgenson E; McBride RB; Graff RE; McGuire V; Achacoso N; Acton L; Liang RY; Lipson JA; Rubin DL; Yaffe MJ; Easton DF; Schaefer C; Risch N; Whittemore AS; Habel LA | October 9, 2020 | PubMed abstract

Genome-wide association studies (GWAS) have identified an abundance of genetic loci associated with complex traits and diseases. In contrast, in-depth characterization of an individual genetic signal is rarely available. Here, we focus on the genetic variant rs2168518 in 15q24.1 previously associated with age-related macular degeneration (AMD), but only with suggestive evidence. In a two-step procedure, we initially conducted a series of association analyses to further delineate the association of rs2168518 with AMD but also with other complex phenotypes by using large independent datasets from the International AMD Genomics Consortium (IAMDGC) and the UK Biobank. We then performed a functional annotation with reference to gene expression regulation based on data from the Genotype-Tissue Expression (GTEx) project and RegulomeDB. Association analysis revealed a gender-specific association with male AMD patients and an association predominantly with choroidal neovascularization. Further, the AMD association colocalizes with an association signal of several blood pressure-related phenotypes and with the gene expression regulation of CYP1A1, a member of the cytochrome P450 superfamily of monooxygenases. Functional annotation revealed altered transcription factor (TF) binding sites for gender-specific TFs, including SOX9 and SRY. In conclusion, the pleiotropic 15q24.1 association signal suggests a shared mechanism between blood pressure regulation and choroidal neovascularization with a potential involvement of CYP1A1.

Authors: Kiel, Christina; Strunz, Tobias; International Amd Genomics Consortium Project Manager Susan Blanton Iamdgc, null; Grassmann, Felix; Weber, Bernhard H. F. | October 8, 2020 | PubMed abstract

Much of the heritable risk of renal cell carcinoma (RCC) associated with common genetic variation is unexplained. New analytic approaches have been developed to increase the discovery of risk variants in genome-wide association studies (GWAS), including multi-locus testing through pathway analysis. We conducted a pathway analysis using GWAS summary data from six previous scans (10,784 cases and 20,406 controls) and evaluated 3,678 pathways and gene sets drawn from the Molecular Signatures Database. To replicate findings, we analyzed GWAS summary data from the UK Biobank (903 cases and 451,361 controls) and the Genetic Epidemiology Research on Adult Health and Aging cohort (317 cases and 50,511 controls). We identified 14 pathways/gene sets associated with RCC in both the discovery (P < 1.36 × 10-5, the Bonferroni correction threshold) and replication (P < 0.05) sets, 10 of which include components of the PI3K/AKT pathway. In tests across 2,035 genes in these pathways, associations (Bonferroni corrected P < 2.46 × 10-5 in discovery and replication sets combined) were observed for CASP9, TIPIN, and CDKN2C. The strongest SNP signal was for rs12124078 (P Discovery = 2.6 × 10-5; P Replication = 1.5 × 10-4; P Combined = 6.9 × 10-8), a CASP9 expression quantitative trait locus. Our pathway analysis implicates genetic variation within the PI3K/AKT pathway as a source of RCC heritability and identifies several promising novel susceptibility genes, including CASP9, which warrant further investigation. Our findings illustrate the value of pathway analysis as a complementary approach to analyzing GWAS data.

Authors: Purdue MP; Song L; Scélo G; Houlston RS; Wu X; Sakoda LC; Thai K; Graff RE; Rothman N; Brennan P; Chanock SJ; Yu K | October 1, 2020 | PubMed abstract

Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Authors: Zhong J; Jermusyk A; Wu L; Hoskins JW; Collins I; Mocci E; Zhang M; Song L; Chung CC; Zhang T; Xiao W; Albanes D; Andreotti G; Arslan AA; Babic A; Bamlet WR; Beane-Freeman L; Berndt S; Borgida A; Bracci PM; Brais L; Brennan P; Bueno-de-Mesquita B; Buring J; Canzian F; Childs EJ; Cotterchio M; Du M; Duell EJ; Fuchs C; Gallinger S; Gaziano JM; Giles GG; Giovannucci E; Goggins M; Goodman GE; Goodman PJ; Haiman C; Hartge P; Hasan M; Helzlsouer KJ; Holly EA; Klein EA; Kogevinas M; Kurtz RJ; LeMarchand L; Malats N; Männistö S; Milne R; Neale RE; Ng K; Obazee O; Oberg AL; Orlow I; Patel AV; Peters U; Porta M; Rothman N; Scelo G; Sesso HD; Severi G; Sieri S; Silverman D; Sund M; Tjønneland A; Thornquist MD; Tobias GS; Trichopoulou A; Van Den Eeden SK; Visvanathan K; Wactawski-Wende J; Wentzensen N; White E; Yu H; Yuan C; Zeleniuch-Jacquotte A; Hoover R; Brown K; Kooperberg C; Risch HA; Jacobs EJ; Li D; Yu K; Shu XO; Chanock SJ; Wolpin BM; Stolzenberg-Solomon RZ; Chatterjee N; Klein AP; Smith JP; Kraft P; Shi J; Petersen GM; Zheng W; Amundadottir LT | October 1, 2020 | PubMed abstract

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

Authors: Rashkin SR; Graff RE; Kachuri L; Thai KK; Alexeeff SE; Blatchins MA; Cavazos TB; Corley DA; Emami NC; Hoffman JD; Jorgenson E; Kushi LH; Meyers TJ; Van Den Eeden SK; Ziv E; Habel LA; Hoffmann TJ; Sakoda LC; Witte JS | September 4, 2020 | PubMed abstract

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Authors: Chen MH; Raffield LM; Mousas A; Sakaue S; Huffman JE; Moscati A; Trivedi B; Jiang T; Akbari P; Vuckovic D; Bao EL; Zhong X; Manansala R; Laplante V; Chen M; Lo KS; Qian H; Lareau CA; Beaudoin M; Hunt KA; Akiyama M; Bartz TM; Ben-Shlomo Y; Beswick A; Bork-Jensen J; Bottinger EP; Brody JA; van Rooij FJA; Chitrala K; Cho K; Choquet H; Correa A; Danesh J; Di Angelantonio E; Dimou N; Ding J; Elliott P; Esko T; Evans MK; Floyd JS; Broer L; Grarup N; Guo MH; Greinacher A; Haessler J; Hansen T; Howson JMM; Huang QQ; Huang W; Jorgenson E; Kacprowski T; Kähönen M; Kamatani Y; Kanai M; Karthikeyan S; Koskeridis F; Lange LA; Lehtimäki T; Lerch MM; Linneberg A; Liu Y; Lyytikäinen LP; Manichaikul A; Martin HC; Matsuda K; Mohlke KL; Mononen N; Murakami Y; Nadkarni GN; Nauck M; Nikus K; Ouwehand WH; Pankratz N; Pedersen O; Preuss M; Psaty BM; Raitakari OT; Roberts DJ; Rich SS; Rodriguez BAT; Rosen JD; Rotter JI; Schubert P; Spracklen CN; Surendran P; Tang H; Tardif JC; Trembath RC; Ghanbari M; Völker U; Völzke H; Watkins NA; Zonderman AB; VA Million Veteran Program; Wilson PWF; Li Y; Butterworth AS; Gauchat JF; Chiang CWK; Li B; Loos RJF; Astle WJ; Evangelou E; van Heel DA; Sankaran VG; Okada Y; Soranzo N; Johnson AD; Reiner AP; Auer PL; Lettre G | September 3, 2020 | PubMed abstract

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Authors: Vuckovic D; Bao EL; Akbari P; Lareau CA; Mousas A; Jiang T; Chen MH; Raffield LM; Tardaguila M; Huffman JE; Ritchie SC; Megy K; Ponstingl H; Penkett CJ; Albers PK; Wigdor EM; Sakaue S; Moscati A; Manansala R; Lo KS; Qian H; Akiyama M; Bartz TM; Ben-Shlomo Y; Beswick A; Bork-Jensen J; Bottinger EP; Brody JA; van Rooij FJA; Chitrala KN; Wilson PWF; Choquet H; Danesh J; Di Angelantonio E; Dimou N; Ding J; Elliott P; Esko T; Evans MK; Felix SB; Floyd JS; Broer L; Grarup N; Guo MH; Guo Q; Greinacher A; Haessler J; Hansen T; Howson JMM; Huang W; Jorgenson E; Kacprowski T; Kähönen M; Kamatani Y; Kanai M; Karthikeyan S; Koskeridis F; Lange LA; Lehtimäki T; Linneberg A; Liu Y; Lyytikäinen LP; Manichaikul A; Matsuda K; Mohlke KL; Mononen N; Murakami Y; Nadkarni GN; Nikus K; Pankratz N; Pedersen O; Preuss M; Psaty BM; Raitakari OT; Rich SS; Rodriguez BAT; Rosen JD; Rotter JI; Schubert P; Spracklen CN; Surendran P; Tang H; Tardif JC; Ghanbari M; Völker U; Völzke H; Watkins NA; Weiss S; VA Million Veteran Program; Cai N; Kundu K; Watt SB; Walter K; Zonderman AB; Cho K; Li Y; Loos RJF; Knight JC; Georges M; Stegle O; Evangelou E; Okada Y; Roberts DJ; Inouye M; Johnson AD; Auer PL; Astle WJ; Reiner AP; Butterworth AS; Ouwehand WH; Lettre G; Sankaran VG; Soranzo N | September 3, 2020 | PubMed abstract

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.

Authors: Thomas M; Sakoda LC; Hoffmeister M; Rosenthal EA; Lee JK; van Duijnhoven FJB; Platz EA; Wu AH; Dampier CH; de la Chapelle A; Wolk A; Joshi AD; Burnett-Hartman A; Gsur A; Lindblom A; Castells A; Win AK; Namjou B; Van Guelpen B; Tangen CM; He Q; Li CI; Schafmayer C; Joshu CE; Ulrich CM; Bishop DT; Buchanan DD; Schaid D; Drew DA; Muller DC; Duggan D; Crosslin DR; Albanes D; Giovannucci EL; Larson E; Qu F; Mentch F; Giles GG; Hakonarson H; Hampel H; Stanaway IB; Figueiredo JC; Huyghe JR; Minnier J; Chang-Claude J; Hampe J; Harley JB; Visvanathan K; Curtis KR; Offit K; Li L; Le Marchand L; Vodickova L; Gunter MJ; Jenkins MA; Slattery ML; Lemire M; Woods MO; Song M; Murphy N; Lindor NM; Dikilitas O; Pharoah PDP; Campbell PT; Newcomb PA; Milne RL; MacInnis RJ; Castellví-Bel S; Ogino S; Berndt SI; Bézieau S; Thibodeau SN; Gallinger SJ; Zaidi SH; Harrison TA; Keku TO; Hudson TJ; Vymetalkova V; Moreno V; Martín V; Arndt V; Wei WQ; Chung W; Su YR; Hayes RB; White E; Vodicka P; Casey G; Gruber SB; Schoen RE; Chan AT; Potter JD; Brenner H; Jarvik GP; Corley DA; Peters U; Hsu L | September 3, 2020 | PubMed abstract

To evaluate the association of the Genomic Prostate Score (GPS) assay result with biochemical recurrence (BCR), distant metastases (DM), and prostate-specific death (PCD) in unfavorable intermediate (UFI) risk prostate cancer patients. The GPS assay is used to help guide management decisions for newly diagnosed low and favorable intermediate (FI) risk disease. GPS results from 2 studies (Center for Prostate Disease Research [CPDR]; Kaiser Permanente Northern California [KPNC]) in men treated with radical prostatectomy were analyzed to determine associations of the GPS result with BCR, DM, and PCD in UFI risk disease. Analyses included 299 intermediate risk prostate patients, 175 of whom had UFI risk disease (KPNC = 103; CPDR = 72). The GPS result as a dichotomous value (≤40 vs >40) was a significant predictor of BCR in UFI patients in multivariate analyses (hazard ratio [HR] 6.0; 95% confidence interval [CI] 2.0-22.4; P = .0035; CPDR). The GPS result was a strong predictor of all 3 endpoints in multivariate analyses (BCR HR 7.1; 95% CI 5.7-8.8; P < .0001; DM HR 5.4; 95% CI 3.8-7.8; P < .0001; PCD HR 3.4; 95% CI 1.5-8.9; P = .006; KPNC). UFI patients with GPS >40 had outcomes consistent with high-risk disease, whereas UFI patients with GPS ≤40 had outcomes similar to FI risk patients (CPDR/KPNC). The GPS result was a strong independent predictor of BCR, DM, and PCD in intermediate risk prostate cancer. UFI patients with GPS >40 have a poor prognosis and may benefit from additional therapeutic options.

Authors: Cullen J; Kuo HC; Shan J; Lu R; Aboushwareb T; Van Den Eeden SK | September 1, 2020 | PubMed abstract

Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated. We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction. The association between minor allele of rs7200950 (ACD) with colorectal cancer-specific survival varied significantly by smoking pack-years (corrected P = 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer-specific survival in women but not in men. Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted. Our study found a gene-smoking and gene-sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.

Authors: Yin H; Hardikar S; Lindstroem S; Hsu L; Anderson KE; Banbury BL; Berndt SI; Chan AT; Giovanucci EL; Harrison TA; Joshi AD; Nan H; Potter JD; Sakoda LC; Slattery ML; Schoen RE; White E; Peters U; Newcomb PA | September 1, 2020 | PubMed abstract

Authors: Kim Y; Jorgenson E; Asgari MM | September 1, 2020 | PubMed abstract

The role of cytochrome P450 (CYP)2C9 and CYP2C19 genetic variation in risk for phenytoin-induced cutaneous adverse drug events is not well understood independently of the human leukocyte antigen B (HLA-B)*15:02 risk allele. In the multi-ethnic resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005 and 2017. These participants included 21 people (5%) who self-identified as Asian, 18 (5%) as black, 29 (8%) as white Hispanic, and 308 (81%) as white non-Hispanic. We identified 264 (69%) CYP2C9*1/*1, 77 (20%) CYP2C9*1/*2, and 29 (8%) CYP2C9*1/*3. We also determined CYP2C19 genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 participants (8%) with phenytoin-induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with CYP2C9*1/*3 or CYP2C9*2/*2 genotypes were more likely to develop cutaneous adverse events compared with CYP2C9*1/*1 participants (odds ratio 4.47; 95% confidence interval 1.64-11.69; P < 0.01). Among participants with low-intermediate and poor CYP2C9 metabolizer genotypes, eight (22%) who also had extensive and rapid CYP2C19 metabolizer genotypes experienced cutaneous adverse events, compared with none of those who also had intermediate CYP2C19 metabolizer genotypes (P = 0.17). Genetic variation reducing CYP2C9 metabolic activity may increase risk for phenytoin-induced cutaneous adverse events in the absence of the HLA-B*15:02 risk allele.

Authors: Fohner AE; Rettie AE; Thai KK; Ranatunga DK; Lawson BL; Liu VX; Schaefer CA | September 1, 2020 | PubMed abstract

Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported. Here, we conducted a genome-wide association study (GWAS) of EF in 26 638 adults from the Genetic Epidemiology Research on Adult Health and Aging and the UK Biobank cohorts. A meta-analysis combining results from Genetic Epidemiology Research on Adult Health and Aging and UK Biobank identified a novel locus: TMEM40 on chromosome 3p25 (rs11719526; β=0.47 and P=3.10×10-8) that replicated in Biobank Japan and confirmed recent findings implicating the BAG3 locus on chromosome 10q26 in EF variation, with the strongest association observed for rs17617337 (β=-0.83 and P=8.24×10-17). Although the minor allele frequencies of TMEM40 rs11719526 were generally common (between 0.13 and 0.44) in different ethnic groups, BAG3 rs17617337 was rare (minor allele frequencies<0.05) in Asian and African ancestry populations. These associations were slightly attenuated, after considering antecedent cardiac conditions (ie, heart failure/cardiomyopathy, hypertension, myocardial infarction, atrial fibrillation, valvular disease, and revascularization procedures). This suggests that the effects of the lead variants at TMEM40 or BAG3 on EF are largely independent of these conditions. In this large and multiethnic study, we identified 2 loci, TMEM40 and BAG3, associated with EF at a genome-wide significance level. Identifying and understanding the genetic determinants of EF is important to better understand the pathophysiology of this strong correlate of cardiac outcomes and to help target the development of future therapies.

Authors: Choquet H; Thai KK; Jiang C; Ranatunga DK; Hoffmann TJ; Go AS; Lindsay AC; Ehm MG; Waterworth DM; Risch N; Schaefer C | August 1, 2020 | PubMed abstract

Genetic testing has increased over the last decade due to growth in the number of clinical and direct-to-consumer (DTC) tests. However, there is uncertainty about how increased DTC genetic testing affects disparities. Between November 2017 and February 2018, a nationwide electronic survey on experiences with genetic testing was conducted among adult Kaiser Permanente members. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals comparing receipt of clinical and DTC genetic testing between groups by race and ethnicity. Invitations were sent to 57,331 members, and 10,369 surveys were completed. 22% of respondents had received genetic testing (17% DTC and 5% provider-ordered). Non-Hispanic Whites were more likely than other groups to have clinical genetic testing but were similar to Hispanics and non-Hispanic Blacks in rates of DTC genetic testing. Among those who received any health-related genetic test, 10% reported abnormal results. Of these, non-Hispanic Whites were more likely than other racial/ethnic groups to speak to a medical professional about abnormal results. Results suggest that racial/ethnic disparities in the use of clinical genetic services persist. Additional research is needed to identify lessons learned from DTC genetic testing that may increase equity in the use of clinical genetic services.

Authors: Carroll NM; Blum-Barnett E; Madrid SD; Jonas C; Janes K; Alvarado M; Bedoy R; Paolino V; Aziz N; McGlynn EA; Burnett-Hartman AN | August 1, 2020 | PubMed abstract

Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of ‘expressed’ genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.

Authors: Nandakumar P; Lee D; Hoffmann TJ; Ehret GB; Arking D; Ranatunga D; Li M; Grove ML; Boerwinkle E; Schaefer C; Kwok PY; Iribarren C; Risch N; Chakravarti A | July 21, 2020 | PubMed abstract

Central corneal thickness (CCT) is one of the most heritable human traits, with broad-sense heritability estimates ranging between 0.68 to 0.95. Despite the high heritability and numerous previous association studies, only 8.5% of CCT variance is currently explained. Here, we report the results of a multiethnic meta-analysis of available genome-wide association studies in which we find association between CCT and 98 genomic loci, of which 41 are novel. Among these loci, 20 were significantly associated with keratoconus, and one (RAPSN rs3740685) was significantly associated with glaucoma after Bonferroni correction. Two-sample Mendelian randomization analysis suggests that thinner CCT does not causally increase the risk of primary open-angle glaucoma. This large CCT study explains up to 14.2% of CCT variance and increases substantially our understanding of the etiology of CCT variation. This may open new avenues of investigation into human ocular traits and their relationship to the risk of vision disorders.

Authors: Choquet H; Melles RB; Yin J; Hoffmann TJ; Thai KK; Kvale MN; Banda Y; Hardcastle AJ; Tuft SJ; Glymour MM; Schaefer C; Risch N; Nair KS; Hysi PG; Jorgenson E | June 11, 2020 | PubMed abstract

Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer-specific survival. Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer-specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer. The 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D-binding protein) was associated with poorer colorectal cancer-specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86-2.78] and colorectal cancer-specific mortality (HR = 1.76; 95% CI, 0.86-3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45-7.33; P heterogeneity = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50-11.43, P heterogeneity = 0.02). Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer-specific survival, although power might have been an issue. Further studies are warranted to investigate the association in specific subgroups.

Authors: Neumeyer S; Butterbach K; Banbury BL; Berndt SI; Campbell PT; Chlebowski RT; Chan AT; Giovannucci EL; Joshi AD; Ogino S; Song M; McCullough ML; Maalmi H; Manson JE; Sakoda LC; Schoen RE; Slattery ML; White E; Win AK; Figueiredo JC; Hopper JL; Macrae FA; Peters U; Brenner H; Hoffmeister M; Newcomb PA; Chang-Claude J | June 1, 2020 | PubMed abstract

Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. To identify novel genetic loci and pathways associated with AS. This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.

Authors: Chen HY; Cairns BJ; Small AM; Burr HA; Ambikkumar A; Martinsson A; Thériault S; Munter HM; Steffen B; Zhang R; Levinson RT; Shaffer CM; Rong J; Sonestedt E; Dufresne L; Ljungberg J; Näslund U; Johansson B; Ranatunga DK; Whitmer RA; Budoff MJ; Nguyen A; Vasan RS; Larson MG; Harris WS; Damrauer SM; Stark KD; Boekholdt SM; Wareham NJ; Pibarot P; Arsenault BJ; Mathieu P; Gudnason V; O'Donnell CJ; Rotter JI; Tsai MY; Post WS; Clarke R; Söderberg S; Bossé Y; Wells QS; Smith JG; Rader DJ; Lathrop M; Engert JC; Thanassoulis G | June 1, 2020 | PubMed abstract

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

Authors: Ferreira MAR; Vonk JM; Baurecht H; Marenholz I; Tian C; Hoffman JD; Helmer Q; Tillander A; Ullemar V; Lu Y; Grosche S; Rüschendorf F; Granell R; Brumpton BM; Fritsche LG; Bhatta L; Gabrielsen ME; Nielsen JB; Zhou W; Hveem K; Langhammer A; Holmen OL; Løset M; Abecasis GR; Willer CJ; Emami NC; Cavazos TB; Witte JS; Szwajda A; 23andMe Research Team; collaborators of the SHARE study; Hinds DA; Hübner N; Weidinger S; Magnusson PK; Jorgenson E; Karlsson R; Paternoster L; Boomsma DI; Almqvist C; Lee YA; Koppelman GH | June 1, 2020 | PubMed abstract

More than 180 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified; these SNPs can be combined into polygenic risk scores (PRS) to predict breast cancer risk. Because most SNPs were identified in predominantly European populations, little is known about the performance of PRS in non-Europeans. We tested the performance of a 180-SNP PRS in Latinas, a large ethnic group with variable levels of Indigenous American, European, and African ancestry. We conducted a pooled case-control analysis of US Latinas and Latin American women (4658 cases and 7622 controls). We constructed a 180-SNP PRS consisting of SNPs associated with breast cancer risk (P < 5 × 10-8). We evaluated the association between the PRS and breast cancer risk using multivariable logistic regression, and assessed discrimination using an area under the receiver operating characteristic curve. We also assessed PRS performance across quartiles of Indigenous American genetic ancestry. All statistical tests were two-sided. Of 180 SNPs tested, 142 showed directionally consistent associations compared with European populations, and 39 were nominally statistically significant (P < .05). The PRS was associated with breast cancer risk, with an odds ratio per SD increment of 1.58 (95% confidence interval [CI = 1.52 to 1.64) and an area under the receiver operating characteristic curve of 0.63 (95% CI = 0.62 to 0.64). The discrimination of the PRS was similar between the top and bottom quartiles of Indigenous American ancestry. The 180-SNP PRS predicts breast cancer risk in Latinas, with similar performance as reported for Europeans. The performance of the PRS did not vary substantially according to Indigenous American ancestry.

Authors: Shieh Y; Fejerman L; Lott PC; Marker K; Sawyer SD; Hu D; Huntsman S; Torres J; Echeverry M; Bohórquez ME; Martínez-Chéquer JC; Polanco-Echeverry G; Estrada-Flórez AP; COLUMBUS Consortium; Haiman CA; John EM; Kushi LH; Torres-Mejía G; Vidaurre T; Weitzel JN; Zambrano SC; Carvajal-Carmona LG; Ziv E; Neuhausen SL | June 1, 2020 | PubMed abstract

Recent large-scale GWAS and large epidemiologic studies have accelerated the discovery of genes and environmental factors that contribute to the risk of keratinocyte carcinoma (KC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This Review summarizes the genomic regions associated with SCC and BCC risk, examines the genetic overlap between SCC and BCC, and discusses biological pathways involved in SCC and BCC development. Next, we review environmental factors that are associated with KC risk, including those that are shared between SCC and BCC as well as others that associated with only one type of KC. We conclude with a critical appraisal of current research and potential directions for future research.

Authors: Choquet H; Ashrafzadeh S; Kim Y; Asgari MM; Jorgenson E | May 21, 2020 | PubMed abstract

Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10-5 ), PSMC5 (P = 4.51 × 10-4 ) and CD33 (P = 2.71 × 10-4 ) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10-5 ) and SCN1B (P = 2.76 × 10-4 ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10-5 ). Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

Authors: Xia Z; Su YR; Petersen P; Qi L; Kim AE; Figueiredo JC; Lin Y; Nan H; Sakoda LC; Albanes D; Berndt SI; Bézieau S; Bien S; Buchanan DD; Casey G; Chan AT; Conti DV; Drew DA; Gallinger SJ; Gauderman WJ; Giles GG; Gruber SB; Gunter MJ; Hoffmeister M; Jenkins MA; Joshi AD; Le Marchand L; Lewinger JP; Li L; Lindor NM; Moreno V; Murphy N; Nassir R; Newcomb PA; Ogino S; Rennert G; Song M; Wang X; Wolk A; Woods MO; Brenner H; White E; Slattery ML; Giovannucci EL; Chang-Claude J; Pharoah PDP; Hsu L; Campbell PT; Peters U | May 1, 2020 | PubMed abstract

Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood. We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis. Alcohol use was positively associated with PD (P trend = 0.01), unassociated with DA (P trend = 0.23), and inversely associated with NDA (P trend = 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (P trend = 0.0008), unassociated with DA (P trend = 0.93), and positively associated with NDA (P trend<0.0001). These trends were stronger in normal and overweight women than in obese women. These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA. PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health.

Authors: McBride RB; Fei K; Rothstein JH; Alexeeff SE; Song X; Sakoda LC; McGuire V; Achacoso N; Acton L; Liang RY; Lipson JA; Yaffe MJ; Rubin DL; Whittemore AS; Habel LA; Sieh W | May 1, 2020 | PubMed abstract

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.

Authors: Hysi PG; Choquet H; Khawaja AP; Wojciechowski R; Tedja MS; Yin J; Simcoe MJ; Patasova K; Mahroo OA; Thai KK; Cumberland PM; Melles RB; Verhoeven VJM; Vitart V; Segre A; Stone RA; Wareham N; Hewitt AW; Mackey DA; Klaver CCW; MacGregor S; Consortium for Refractive Error and Myopia; Khaw PT; Foster PJ; UK Eye and Vision Consortium; Guggenheim JA; 23andMe Inc.; Rahi JS; Jorgenson E; Hammond CJ | April 1, 2020 | PubMed abstract

Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

Authors: Archambault AN; Su YR; Jeon J; Thomas M; Lin Y; Conti DV; Win AK; Sakoda LC; Lansdorp-Vogelaar I; Peterse EFP; Zauber AG; Duggan D; Holowatyj AN; Huyghe JR; Brenner H; Cotterchio M; Bézieau S; Schmit SL; Edlund CK; Southey MC; MacInnis RJ; Campbell PT; Chang-Claude J; Slattery ML; Chan AT; Joshi AD; Song M; Cao Y; Woods MO; White E; Weinstein SJ; Ulrich CM; Hoffmeister M; Bien SA; Harrison TA; Hampe J; Li CI; Schafmayer C; Offit K; Pharoah PD; Moreno V; Lindblom A; Wolk A; Wu AH; Li L; Gunter MJ; Gsur A; Keku TO; Pearlman R; Bishop DT; Castellví-Bel S; Moreira L; Vodicka P; Kampman E; Giles GG; Albanes D; Baron JA; Berndt SI; Brezina S; Buch S; Buchanan DD; Trichopoulou A; Severi G; Chirlaque MD; Sánchez MJ; Palli D; Kühn T; Murphy N; Cross AJ; Burnett-Hartman AN; Chanock SJ; de la Chapelle A; Easton DF; Elliott F; English DR; Feskens EJM; FitzGerald LM; Goodman PJ; Hopper JL; Hudson TJ; Hunter DJ; Jacobs EJ; Joshu CE; Küry S; Markowitz SD; Milne RL; Platz EA; Rennert G; Rennert HS; Schumacher FR; Sandler RS; Seminara D; Tangen CM; Thibodeau SN; Toland AE; van Duijnhoven FJB; Visvanathan K; Vodickova L; Potter JD; Männistö S; Weigl K; Figueiredo J; Martín V; Larsson SC; Parfrey PS; Huang WY; Lenz HJ; Castelao JE; Gago-Dominguez M; Muñoz-Garzón V; Mancao C; Haiman CA; Wilkens LR; Siegel E; Barry E; Younghusband B; Van Guelpen B; Harlid S; Zeleniuch-Jacquotte A; Liang PS; Du M; Casey G; Lindor NM; Le Marchand L; Gallinger SJ; Jenkins MA; Newcomb PA; Gruber SB; Schoen RE; Hampel H; Corley DA; Hsu L; Peters U; Hayes RB | April 1, 2020 | PubMed abstract

Latinos represent <1% of samples analyzed to date in genome-wide association studies of cancer. The clinical value of genetic information in guiding personalized medicine in populations of non-European ancestry will require additional discovery and risk locus characterization efforts across populations. In the present study, we performed a GWAS of prostate cancer (PrCa) in 2,820 Latino PrCa cases and 5,293 controls to search for novel PrCa risk loci and to examine the generalizability of known PrCa risk loci in Latino men. We also conducted a genetic admixture-mapping scan to identify PrCa risk alleles associated with local ancestry. Genome-wide significant associations were observed with 84 variants all located at the known PrCa risk regions at 8q24 (128.484-128.548) and 10q11.22 (MSMB gene). In admixture mapping, we observed genome-wide significant associations with local African ancestry at 8q24. Of the 162 established PrCa risk variants that are common in Latino men, 135 (83.3%) had effects that were directionally consistent as previously reported, among which 55 (34.0%) were statistically significant with p < 0.05. A polygenic risk model of the known PrCa risk variants showed that, compared to men with average risk (25th-75th percentile of the polygenic risk score distribution), men in the top 10% had a 3.19-fold (95% CI: 2.65, 3.84) increased PrCa risk. In conclusion, we found that the known PrCa risk variants can effectively stratify PrCa risk in Latino men. Larger studies in Latino populations will be required to discover and characterize genetic risk variants for PrCa and improve risk stratification for this population.

Authors: Du Z; Hopp H; Ingles SA; Huff C; Sheng X; Weaver B; Stern M; Hoffmann TJ; John EM; Van Den Eeden SK; Strom S; Leach RJ; Thompson IM; Witte JS; Conti DV; Haiman CA | April 1, 2020 | PubMed abstract

Asthma affects more than 300 million people in the world, costs over $80 billion annually in the United States, and is efficaciously treated with inhaled corticosteroids (ICS). To our knowledge, no studies have examined the real-world effectiveness of ICS, including the combination therapy consisting of ICS and long-acting beta agonists (LABAs), and patterns of use over a 15-year time period. We used data from the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort which comprises longitudinal electronic health record data of over 100,000 people. Data included longitudinal asthma-related events, such as ambulatory office visits, hospitalizations, emergency department (ED) visits, and fills of ICS and ICS-LABA combination. Asthma exacerbations were defined as an asthma-related ED visit, hospitalization, or oral corticosteroid (OCS) burst. We used an expected-value approach to determine ICS and ICS-LABA coverage over exacerbation events. We compared rates of exacerbation of subjects on ICS or ICS-LABAs to their own rates of exacerbation when off controller medications. We found ICS-LABA therapy had significant effects, reducing all types of exacerbations per day by a factor of 1.76 (95% CI (1.06, 2.93), p = 0.03) and, specifically, bursts per day by a factor of 1.91 (95% CI (1.04, 3.53), p = 0.037). In conclusion, ICS-LABA therapy was significantly associated with fewer asthma-related exacerbations in a large population of individuals with asthma who were followed for 15 years.

Authors: McGeachie MJ; Wang AL; Lutz SM; Sordillo JE; Weiss ST; Tantisira KG; Iribarren C; Lu MX; Wu AC | March 18, 2020 | PubMed abstract

The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

Authors: Glanville KP; Coleman JRI; Hanscombe KB; Euesden J; Choi SW; Purves KL; Breen G; Air TM; Andlauer TFM; Baune BT; Binder EB; Blackwood DHR; Boomsma DI; Buttenschøn HN; Colodro-Conde L; Dannlowski U; Direk N; Dunn EC; Forstner AJ; de Geus EJC; Grabe HJ; Hamilton SP; Jones I; Jones LA; Knowles JA; Kutalik Z; Levinson DF; Lewis G; Lind PA; Lucae S; Magnusson PK; McGuffin P; McIntosh AM; Milaneschi Y; Mors O; Mostafavi S; Müller-Myhsok B; Pedersen NL; Penninx BWJH; Potash JB; Preisig M; Ripke S; Shi J; Shyn SI; Smoller JW; Streit F; Sullivan PF; Tiemeier H; Uher R; Van der Auwera S; Weissman MM; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; O'Reilly PF; Lewis CM | March 1, 2020 | PubMed abstract

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.

Authors: Sarin KY; Lin Y; Daneshjou R; Ziyatdinov A; Thorleifsson G; Rubin A; Pardo LM; Wu W; Khavari PA; Uitterlinden A; Nijsten T; Toland AE; Olafsson JH; Sigurgeirsson B; Thorisdottir K; Jorgensen E; Whittemore AS; Kraft P; Stacey SN; Stefansson K; Asgari MM; Han J | February 10, 2020 | PubMed abstract

In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (SORT/CELSR2/PSRC1, LPA, SLCO1B1, APOE, APOB, and SMARCA4/LDLR). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (LPA, APOE, and SLCO1B1). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (SORT/CELSR2/PSRC1, APOB, SMARCA4/LDLR) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.

Authors: Oni-Orisan A; Haldar T; Ranatunga DK; Medina MW; Schaefer C; Krauss RM; Iribarren C; Risch N; Hoffmann TJ | January 1, 2020 | PubMed abstract

Most genetics studies lack the diversity necessary to ensure that all groups benefit from genetic research. To explore facilitators and barriers to genetic research participation. We conducted a survey on genetics in research and healthcare from November 15, 2017 to February 28, 2018 among adult Kaiser Permanente (KP) members who had been invited to participate in the KP biobank (KP Research Bank). We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing the willingness to participate in genetic research under different return of results scenarios and genetic discrimination concerns between groups, according to their demographic characteristics. A total of 57,331 KP members were invited to participate, and 10,369 completed the survey (18% response rate). Respondents were 65% female, 44% non-Hispanic White (NH White), 22% Asian/Native Hawaiian or other Pacific Islander (Asian/PI), 19% non-Hispanic Black (NH Black), and 16% Hispanic. Respondents willing to participate in genetic research ranged from 22% with no results returned to 87% if health-related genetic results were returned. We also found variation by race/ethnicity; when no results were to be returned, Asian/PIs, Hispanics, and NH Blacks were less likely to want to participate than NH Whites (p < 0.05). However, when results were returned, disparities in the willingness to participate disappeared for NH Blacks and Hispanics. Genetic discrimination concerns were more prevalent in Asian/PIs, Hispanics, and NH Blacks than in NH Whites (p < 0.05). Policies that prohibit the return of results and do not address genetic discrimination concerns may contribute to a greater underrepresentation of diverse groups in genetic research.

Authors: Burnett-Hartman AN; Blum-Barnett E; Carroll NM; Madrid SD; Jonas C; Janes K; Alvarado M; Bedoy R; Paolino V; Aziz N; McGlynn EA | January 1, 2020 | PubMed abstract

Familial cerebral cavernous malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by brain lesions that can cause hemorrhagic strokes, seizures, and neurological deficits. Carriers of the same genetic mutation can present with variable symptoms and severity of disease, suggesting the influence of modifier factors. Genetic modifiers of CCM1 disease severity have been recently identified and included common genetic variants in inflammatory, immune response, and oxidative stress genes and pathways. Here, we describe the genotyping of CCM1 patients with the same gene mutation (Q455X) using a high-throughput genotyping array optimized for individuals of Hispanic/Latino ancestry. We then review the quality control steps following the genome-wide genotyping. Genome-wide genotyping of larger cohorts of CCM1 patients might reveal additional genetic variants contributing to the disease severity of CCM1.

Authors: Choquet H; Kim H | January 1, 2020 | PubMed abstract

Atopic dermatitis (AD) is more common among African American children. Whether there are racial/ethnic difference among adults with AD and the causes for those disparities are unclear. We sought to examine the relationship between self-reported race/ethnicity and AD and determine whether African genetic ancestry is predictive of these outcomes among African American subjects. We analyzed data from 2 independent multiethnic longitudinal studies: 86,893 subjects aged 18 to 100 years from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and 5467 subjects aged 2 to 26 years from the national Pediatric Eczema Elective Registry (PEER) cohort. The primary outcomes were physician-diagnosed AD in GERA and repeated measures of self-reported disease control among patients with physician-diagnosed AD at 6-month intervals in PEER. We examined whether self-identified African American race/ethnicity was predictive of these outcomes and then tested whether a continuous measure of African genetic ancestry was associated with outcomes within the African American group. AD was more common among self-identified African American subjects than non-Hispanic white subjects in GERA (4.4% vs 2.1%; odds ratio, 2.06; 95% CI, 1.70-2.48) and less well-controlled in PEER subjects (odds of 1-level worse control, 1.91; 95% CI, 1.64-2.22). However, African genetic ancestry was not associated with AD risk or control among self-identified African American subjects in either cohort, nor did an AD polygenic risk score or genetic skin pigment score explain the AD disparities in patients with AD. Ancestry-related genetic effects do not explain increased AD prevalence or poorer disease control among African American subjects.

Authors: Abuabara K; You Y; Margolis DJ; Hoffmann TJ; Risch N; Jorgenson E | January 1, 2020 | PubMed abstract

High alcohol consumption is a risk factor for morbidity and mortality, yet few genetic loci have been robustly associated with alcohol intake. Here, we use U.K. Biobank (n = 125,249) and GERA (n = 47,967) datasets to determine genetic factors associated with extreme population-level alcohol consumption and examine the functional validity of outcomes using model organisms and in silico techniques. We identified six loci attaining genome-wide significant association with alcohol consumption after meta-analysis and meeting our criteria for replication: ADH1B (lead SNP: rs1229984), KLB (rs13130794), BTF3P13 (rs144198753), GCKR (rs1260326), SLC39A8 (rs13107325), and DRD2 (rs11214609). A conserved role in phenotypic responses to alcohol was observed for all genetic targets available for investigation (ADH1B, GCKR, SLC39A8, and KLB) in Caenorhabditis elegans. Evidence of causal links to lung cancer, and shared genetic architecture with gout and hypertension was also found. These findings offer insight into genes, pathways, and relationships for disease risk associated with high alcohol consumption.

Authors: Thompson A; Cook J; Choquet H; Jorgenson E; Yin J; Kinnunen T; Barclay J; Morris AP; Pirmohamed M | January 1, 2020 | PubMed abstract

Over the last decade, genetic studies, including genome-wide association studies (GWAS), have accelerated the discovery of genes and genomic regions contributing to primary open-angle glaucoma (POAG), a leading cause of irreversible vision loss. Here, we review the findings of genetic studies of POAG published in English prior to September 2019. In total, 74 genomic regions have been associated at a genome-wide level of significance with POAG susceptibility. Recent POAG GWAS provide not only insight into global and ethnic-specific genetic risk factors for POAG susceptibility across populations of diverse ancestry, but also important functional insights underlying biological mechanisms of glaucoma pathogenesis. In this review, we also summarize the genetic overlap between POAG, glaucoma endophenotypes, such as intraocular pressure and vertical cup-disc ratio (VCDR), and other eye disorders. We also discuss approaches recently developed to increase power for POAG locus discovery and to predict POAG risk. Finally, we discuss the recent development of POAG gene-based therapies and future strategies to treat glaucoma effectively. Understanding the genetic architecture of POAG is essential for an earlier diagnosis of this common eye disorder, predictive testing of at-risk patients, and design of gene-based targeted medical therapies none of which are currently available. ??: ?????????(POAG)???????????????, ??????, ?????????, ??????????, ???POAG??????????????????2019?9??????????POAG?????????????????, ??74???????POAG???????????POAG? GWAS????????????????POAG????????????, ?????????????????????????????????, ?????POAG???????????, ??????? (??????????) ??????????????????????????????POAG??????????POAG????????, ???????POAG??????????????????????????POAG????????????????????, ??????????????????????????????????????.

Authors: Choquet H; Wiggs JL; Khawaja AP | January 1, 2020 | PubMed abstract

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8×10-15] in African populations, rs11549407 with lower HGB [p = 1.5×10-12] and HCT [p = 8.8×10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

Authors: Kowalski MH; Qian H; Hou Z; Rosen JD; Tapia AL; Shan Y; Jain D; Argos M; Arnett DK; Avery C; Barnes KC; Becker LC; Bien SA; Bis JC; Blangero J; Boerwinkle E; Bowden DW; Buyske S; Cai J; Cho MH; Choi SH; Choquet H; Cupples LA; Cushman M; Daya M; de Vries PS; Ellinor PT; Faraday N; Fornage M; Gabriel S; Ganesh SK; Graff M; Gupta N; He J; Heckbert SR; Hidalgo B; Hodonsky CJ; Irvin MR; Johnson AD; Jorgenson E; Kaplan R; Kardia SLR; Kelly TN; Kooperberg C; Lasky-Su JA; Loos RJF; Lubitz SA; Mathias RA; McHugh CP; Montgomery C; Moon JY; Morrison AC; Palmer ND; Pankratz N; Papanicolaou GJ; Peralta JM; Peyser PA; Rich SS; Rotter JI; Silverman EK; Smith JA; Smith NL; Taylor KD; Thornton TA; Tiwari HK; Tracy RP; Wang T; Weiss ST; Weng LC; Wiggins KL; Wilson JG; Yanek LR; Zöllner S; North KE; Auer PL; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Hematology & Hemostasis Working Group; Raffield LM; Reiner AP; Li Y | December 1, 2019 | PubMed abstract

Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Genetic variants associated with primary open-angle glaucoma. Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

Authors: Genetics of Glaucoma in People of African Descent (GGLAD) Consortium; Hauser MA; Allingham RR; Aung T; Van Der Heide CJ; Taylor KD; Rotter JI; Wang SJ; Bonnemaijer PWM; Williams SE; Abdullahi SM; Abu-Amero KK; Anderson MG; Akafo S; Alhassan MB; Asimadu I; Ayyagari R; Bakayoko S; Nyamsi PB; Bowden DW; Bromley WC; Budenz DL; Carmichael TR; Challa P; Chen YI; Chuka-Okosa CM; Cooke Bailey JN; Costa VP; Cruz DA; DuBiner H; Ervin JF; Feldman RM; Flamme-Wiese M; Gaasterland DE; Garnai SJ; Girkin CA; Guirou N; Guo X; Haines JL; Hammond CJ; Herndon L; Hoffmann TJ; Hulette CM; Hydara A; Igo RP; Jorgenson E; Kabwe J; Kilangalanga NJ; Kizor-Akaraiwe N; Kuchtey RW; Lamari H; Li Z; Liebmann JM; Liu Y; Loos RJF; Melo MB; Moroi SE; Msosa JM; Mullins RF; Nadkarni G; Napo A; Ng MCY; Nunes HF; Obeng-Nyarkoh E; Okeke A; Okeke S; Olaniyi O; Olawoye O; Oliveira MB; Pasquale LR; Perez-Grossmann RA; Pericak-Vance MA; Qin X; Ramsay M; Resnikoff S; Richards JE; Schimiti RB; Sim KS; Sponsel WE; Svidnicki PV; Thiadens AAHJ; Uche NJ; van Duijn CM; de Vasconcellos JPC; Wiggs JL; Zangwill LM; Risch N; Milea D; Ashaye A; Klaver CCW; Weinreb RN; Ashley Koch AE; Fingert JH; Khor CC | November 5, 2019 | PubMed abstract

Acral melanoma is a rare type of melanoma that affects world populations irrespective of skin color and has worse survival than other cutaneous melanomas. It has relatively few single nucleotide mutations without the UV signature of cutaneous melanomas, but instead has a genetic landscape characterized by structural rearrangements and amplifications. BRAF mutations are less common than in other cutaneous melanomas, and knowledge about alternative therapeutic targets is incomplete. To identify alternative therapeutic targets, we performed targeted deep-sequencing on 122 acral melanomas. We confirmed the loss of the tumor suppressors p16 and NF1 by immunohistochemistry in select cases. In addition to BRAF (21.3%), NRAS (27.9%), and KIT (11.5%) mutations, we identified a broad array of MAPK pathway activating alterations, including fusions of BRAF (2.5%), NTRK3 (2.5%), ALK (0.8%), and PRKCA (0.8%), which can be targeted by available inhibitors. Inactivation of NF1 occurred in 18 cases (14.8%). Inactivation of the NF1 cooperating factor SPRED1 occurred in eight cases (6.6%) as an alternative mechanism of disrupting the negative regulation of RAS. Amplifications recurrently affected narrow loci containing PAK1 and GAB2 (n = 27, 22.1%), CDK4 (n = 27, 22.1%), CCND1 (n = 24, 19.7%), EP300 (n = 20, 16.4%), YAP1 (n = 15, 12.3%), MDM2 (n = 13, 10.7%), and TERT (n = 13, 10.7%) providing additional and possibly complementary therapeutic targets. Acral melanomas with BRAFV600E mutations harbored fewer genomic amplifications and were more common in patients with European ancestry. Our findings support a new, molecularly based subclassification of acral melanoma with potential therapeutic implications: BRAFV600E mutant acral melanomas with characteristics similar to nonacral melanomas that could benefit from BRAF inhibitor therapy, and non-BRAFV600E mutant acral melanomas. Acral melanomas without BRAFV600E mutations harbor a broad array of therapeutically relevant alterations. Expanded molecular profiling would increase the detection of potentially targetable alterations for this subtype of acral melanoma.

Authors: Yeh I; Jorgenson E; Shen L; Xu M; North JP; Shain AH; Reuss D; Wu H; Robinson WA; Olshen A; von Deimling A; Kwok PY; Bastian BC; Asgari MM | October 1, 2019 | PubMed abstract

To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment. A retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response. Among 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration [21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; P < 0.01] and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; P < 0.01). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin. CYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.

Authors: Fohner AE; Ranatunga DK; Thai KK; Lawson BL; Risch N; Oni-Orisan A; Jelalian AT; Rettie AE; Liu VX; Schaefer CA | October 1, 2019 | PubMed abstract

Allopurinol, which lowers uric acid (UA) concentration, is increasingly being recognized for its benefits in cardiovascular and renal disease. However, response to allopurinol is variable. We gathered samples from 4,446 multiethnic subjects for a genome-wide association study of allopurinol response. Consistent with previous studies, we observed that the Q141K variant in ABCG2 (rs2231142), which encodes the efflux pump breast cancer resistance protein (BCRP), associated with worse response to allopurinol. However, for the first time this association reached genome-wide level significance (P = 8.06 × 10-11 ). Additionally, we identified a novel association with a variant in GREM2 (rs1934341, P = 3.22 × 10-6 ). In vitro studies identified oxypurinol, the active metabolite of allopurinol, as an inhibitor of the UA transporter GLUT9, suggesting that oxypurinol may modulate UA reabsorption. These results provide strong evidence for a role of BCRP Q141K in allopurinol response, and suggest that allopurinol may have additional hypouricemic effects beyond xanthine oxidase inhibition.

Authors: Brackman DJ; Yee SW; Enogieru OJ; Shaffer C; Ranatunga D; Denny JC; Wei WQ; Kamatani Y; Kubo M; Roden DM; Jorgenson E; Giacomini KM | September 1, 2019 | PubMed abstract

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.

Authors: Emami NC; Kachuri L; Meyers TJ; Das R; Hoffman JD; Hoffmann TJ; Hu D; Shan J; Feng FY; Ziv E; Van Den Eeden SK; Witte JS | July 15, 2019 | PubMed abstract

Beginning in 2005, researchers at Kaiser Permanente Northern California (KPNC) Division of Research developed the Research Program on Genes, Environment, and Health (RPGEH), a research resource of linked biospecimens, health surveys, and electronic health records on more than 200,000 adult KPNC members. This study examined multiple stakeholders’ values and preferences regarding protection of participants’ privacy and wide sharing of participant data by RPGEH. We conducted 45 semi-structured interviews in person or via phone and two focus groups with seven stakeholder groups, including RPGEH participants and decliners who are KPNC members, KPNC research scientists, external scientists, leadership, Human Subjects Research Protection Program staff, and RPGEH Community Advisory Panel members. Three major themes emerged related to: (1) perceived individual and social harms associated with data sharing; (2) concerns to address when governing access to RPGEH data; and (3) impact of a blurred boundary between research and clinical care in the context of biobanking. The study results were considered in the development of RPGEH data governance and motivated the inclusion of KPNC Community Advisory Panel members and ELSI experts on committees that evaluate data access proposals. Our findings can help inform other biobanks going through similar processes developing data sharing and access policies.

Authors: Tai CG; Harris-Wai J; Schaefer C; Liljestrand P; Somkin CP | June 5, 2019 | PubMed abstract

Telomere length (TL) may serve as a biologic marker of aging. We examined neighborhood and individual-level socioeconomic status (SES) in relation to TL. The study included 84,996 non-Hispanic white subjects from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, part of the Research Program on Genes, Environment and Health. Relative TL (T/S) was log2 transformed to improve normality and standardized to have mean 0 and variance 1. Neighborhood SES was measured using the Neighborhood Deprivation Index (NDI), and individual SES was measured by self-reported education level. We fit linear regression models of TL on age, sex, smoking, body mass index, comorbidities, NDI, and education level. We tested for differences in the associations by sex and nonlinearity in the association of NDI with TL. Each SD increase in NDI was associated with a decrease of 0.0192 in standardized TL, 95% confidence interval (CI) = -0.0306, -0.0078. There was no evidence of nonlinearity in the association of NDI with TL. We further found that less than high school education was associated with a decrease of 0.1371 in standardized TL, 95% CI = -0.1919, -0.0823 as compared to a college education. There were no differences in the associations by sex. We found evidence that both lower neighborhood SES and lower individual-level SES are associated with shorter TL among non-Hispanic whites. Our findings suggest that socioeconomic factors may influence aging by contributing to shorter TL.

Authors: Alexeeff SE; Schaefer CA; Kvale MN; Shan J; Blackburn EH; Risch N; Ranatunga DK; Jorgenson E; Hoffmann TJ; Sakoda LC; Quesenberry CP; Van Den Eeden SK | June 1, 2019 | PubMed abstract

Breast density is a modifiable factor that is strongly associated with breast cancer risk. We sought to understand the influence of newer technologies of full-field digital mammography (FFDM) on breast density research and to determine whether results are comparable across studies using FFDM and previous studies using traditional film-screen mammography. We studied 24,840 screening-age (40-74 years) non-Hispanic white women who were participants in the Research Program on Genes, Environment and Health of Kaiser Permanente Northern California and underwent screening mammography with either Hologic (Hologic, Inc., Marlborough, Massachusetts) or General Electric (General Electric Company, Boston, Massachusetts) FFDM machines between 2003 and 2013. We estimated the associations of parity, age at first birth, age at menarche, and menopausal status with percent density and dense area as measured by a single radiological technologist using Cumulus software (Canto Software, Inc., San Francisco, California). We found that associations between reproductive factors and mammographic density measured using processed FFDM images were generally similar in magnitude and direction to those from prior studies using film mammography. Estimated associations for both types of FFDM machines were in the same direction. There was some evidence of heterogeneity in the magnitude of the effect sizes by machine type, which we accounted for using random-effects meta-analysis when combining results. Our findings demonstrate the robustness of quantitative mammographic density measurements across FFDM and film mammography platforms.

Authors: Alexeeff SE; Odo NU; McBride R; McGuire V; Achacoso N; Rothstein JH; Lipson JA; Liang RY; Acton L; Yaffe MJ; Whittemore AS; Rubin DL; Sieh W; Habel LA | June 1, 2019 | PubMed abstract

Onset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis. GWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes. MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling. Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.

Authors: Rhead B; Shao X; Graves JS; Chitnis T; Waldman AT; Lotze T; Schreiner T; Belman A; Krupp L; Greenberg BM; Weinstock-Guttman B; Aaen G; Tillema JM; Rodriguez M; Hart J; Caillier S; Ness J; Harris Y; Rubin J; Candee MS; Gorman M; Benson L; Mar S; Kahn I; Rose J; Casper TC; Quach H; Quach D; Schaefer C; Waubant E; Barcellos LF; US Network of Pediatric MS Centers | June 1, 2019 | PubMed abstract

Authors: Dahlin A; Sordillo JE; Ziniti J; Iribarren C; Lu M; Weiss ST; Tantisira KG; Lu Q; Kan M; Himes BE; Jorgenson E; Wu AC | April 1, 2019 | PubMed abstract

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Authors: Grove, Jakob; Ripke, Stephan; Als, Thomas D.; Mattheisen, Manuel; Walters, Raymond K.; Won, Hyejung; Pallesen, Jonatan; Agerbo, Esben; Andreassen, Ole A.; Anney, Richard; Awashti, Swapnil; Belliveau, Rich; Bettella, Francesco; Buxbaum, Joseph D.; Bybjerg-Grauholm, Jonas; Bækvad-Hansen, Marie; Cerrato, Felecia; Chambert, Kimberly; Christensen, Jane H.; Churchhouse, Claire; Dellenvall, Karin; Demontis, Ditte; De Rubeis, Silvia; Devlin, Bernie; Djurovic, Srdjan; Dumont, Ashley L.; Goldstein, Jacqueline I.; Hansen, Christine S.; Hauberg, Mads Engel; Hollegaard, Mads V.; Hope, Sigrun; Howrigan, Daniel P.; Huang, Hailiang; Hultman, Christina M.; Klei, Lambertus; Maller, Julian; Martin, Joanna; Martin, Alicia R.; Moran, Jennifer L.; Nyegaard, Mette; Nærland, Terje; Palmer, Duncan S.; Palotie, Aarno; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; dPoterba, Timothy; Poulsen, Jesper Buchhave; Pourcain, Beate St; Qvist, Per; Rehnström, Karola; Reichenberg, Abraham; Reichert, Jennifer; Robinson, Elise B.; Roeder, Kathryn; Roussos, Panos; Saemundsen, Evald; Sandin, Sven; Satterstrom, F. Kyle; Davey Smith, George; Stefansson, Hreinn; Steinberg, Stacy; Stevens, Christine R.; Sullivan, Patrick F.; Turley, Patrick; Walters, G. Bragi; Xu, Xinyi; Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium; BUPGEN; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; 23andMe Research Team; Stefansson, Kari; Geschwind, Daniel H.; Nordentoft, Merete; Hougaard, David M.; Werge, Thomas; Mors, Ole; Mortensen, Preben Bo; Neale, Benjamin M.; Daly, Mark J.; Børglum, Anders D. | March 1, 2019 | PubMed abstract

Authors: Jorgenson E; Matharu N; Palmer MR; Yin J; Shan J; Hoffmann TJ; Thai KK; Zhou X; Hotaling JM; Jarvik GP; Ahituv N; Wessells H; Van Den Eeden SK | February 26, 2019 | PubMed abstract

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

Authors: Liu M; Jiang Y; Wedow R; Li Y; Brazel DM; Chen F; Datta G; Davila-Velderrain J; McGuire D; Tian C; Zhan X; 23andMe Research Team; HUNT All-In Psychiatry; Choquet H; Docherty AR; Faul JD; Foerster JR; Fritsche LG; Gabrielsen ME; Gordon SD; Haessler J; Hottenga JJ; Huang H; Jang SK; Jansen PR; Ling Y; Mägi R; Matoba N; McMahon G; Mulas A; Orrù V; Palviainen T; Pandit A; Reginsson GW; Skogholt AH; Smith JA; Taylor AE; Turman C; Willemsen G; Young H; Young KA; Zajac GJM; Zhao W; Zhou W; Bjornsdottir G; Boardman JD; Boehnke M; Boomsma DI; Chen C; Cucca F; Davies GE; Eaton CB; Ehringer MA; Esko T; Fiorillo E; Gillespie NA; Gudbjartsson DF; Haller T; Harris KM; Heath AC; Hewitt JK; Hickie IB; Hokanson JE; Hopfer CJ; Hunter DJ; Iacono WG; Johnson EO; Kamatani Y; Kardia SLR; Keller MC; Kellis M; Kooperberg C; Kraft P; Krauter KS; Laakso M; Lind PA; Loukola A; Lutz SM; Madden PAF; Martin NG; McGue M; McQueen MB; Medland SE; Metspalu A; Mohlke KL; Nielsen JB; Okada Y; Peters U; Polderman TJC; Posthuma D; Reiner AP; Rice JP; Rimm E; Rose RJ; Runarsdottir V; Stallings MC; Stančáková A; Stefansson H; Thai KK; Tindle HA; Tyrfingsson T; Wall TL; Weir DR; Weisner C; Whitfield JB; Winsvold BS; Yin J; Zuccolo L; Bierut LJ; Hveem K; Lee JJ; Munafò MR; Saccone NL; Willer CJ; Cornelis MC; David SP; Hinds DA; Jorgenson E; Kaprio J; Stitzel JA; Stefansson K; Thorgeirsson TE; Abecasis G; Liu DJ; Vrieze S | February 1, 2019 | PubMed abstract

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

Authors: Kilpeläinen TO; Bentley AR; Noordam R; Sung YJ; Schwander K; Winkler TW; Jakupović H; Chasman DI; Manning A; Ntalla I; Aschard H; Brown MR; de Las Fuentes L; Franceschini N; Guo X; Vojinovic D; Aslibekyan S; Feitosa MF; Kho M; Musani SK; Richard M; Wang H; Wang Z; Bartz TM; Bielak LF; Campbell A; Dorajoo R; Fisher V; Hartwig FP; Horimoto ARVR; Li C; Lohman KK; Marten J; Sim X; Smith AV; Tajuddin SM; Alver M; Amini M; Boissel M; Chai JF; Chen X; Divers J; Evangelou E; Gao C; Graff M; Harris SE; He M; Hsu FC; Jackson AU; Zhao JH; Kraja AT; Kühnel B; Laguzzi F; Lyytikäinen LP; Nolte IM; Rauramaa R; Riaz M; Robino A; Rueedi R; Stringham HM; Takeuchi F; van der Most PJ; Varga TV; Verweij N; Ware EB; Wen W; Li X; Yanek LR; Amin N; Arnett DK; Boerwinkle E; Brumat M; Cade B; Canouil M; Chen YI; Concas MP; Connell J; de Mutsert R; de Silva HJ; de Vries PS; Demirkan A; Ding J; Eaton CB; Faul JD; Friedlander Y; Gabriel KP; Ghanbari M; Giulianini F; Gu CC; Gu D; Harris TB; He J; Heikkinen S; Heng CK; Hunt SC; Ikram MA; Jonas JB; Koh WP; Komulainen P; Krieger JE; Kritchevsky SB; Kutalik Z; Kuusisto J; Langefeld CD; Langenberg C; Launer LJ; Leander K; Lemaitre RN; Lewis CE; Liang J; Lifelines Cohort Study; Liu J; Mägi R; Manichaikul A; Meitinger T; Metspalu A; Milaneschi Y; Mohlke KL; Mosley TH; Murray AD; Nalls MA; Nang EK; Nelson CP; Nona S; Norris JM; Nwuba CV; O'Connell J; Palmer ND; Papanicolau GJ; Pazoki R; Pedersen NL; Peters A; Peyser PA; Polasek O; Porteous DJ; Poveda A; Raitakari OT; Rich SS; Risch N; Robinson JG; Rose LM; Rudan I; Schreiner PJ; Scott RA; Sidney SS; Sims M; Smith JA; Snieder H; Sofer T; Starr JM; Sternfeld B; Strauch K; Tang H; Taylor KD; Tsai MY; Tuomilehto J; Uitterlinden AG; van der Ende MY; van Heemst D; Voortman T; Waldenberger M; Wennberg P; Wilson G; Xiang YB; Yao J; Yu C; Yuan JM; Zhao W; Zonderman AB; Becker DM; Boehnke M; Bowden DW; de Faire U; Deary IJ; Elliott P; Esko T; Freedman BI; Froguel P; Gasparini P; Gieger C; Kato N; Laakso M; Lakka TA; Lehtimäki T; Magnusson PKE; Oldehinkel AJ; Penninx BWJH; Samani NJ; Shu XO; van der Harst P; Van Vliet-Ostaptchouk JV; Vollenweider P; Wagenknecht LE; Wang YX; Wareham NJ; Weir DR; Wu T; Zheng W; Zhu X; Evans MK; Franks PW; Gudnason V; Hayward C; Horta BL; Kelly TN; Liu Y; North KE; Pereira AC; Ridker PM; Tai ES; van Dam RM; Fox ER; Kardia SLR; Liu CT; Mook-Kanamori DO; Province MA; Redline S; van Duijn CM; Rotter JI; Kooperberg CB; Gauderman WJ; Psaty BM; Rice K; Munroe PB; Fornage M; Cupples LA; Rotimi CN; Morrison AC; Rao DC; Loos RJF | January 22, 2019 | PubMed abstract

Breast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas. We performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach. We identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10- 8 – 6.0 × 10- 9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2 > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p = 0.0017). Our study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.

Authors: Hoffman J; Fejerman L; Hu D; Huntsman S; Li M; John EM; Torres-Mejia G; Kushi L; Ding YC; Weitzel J; Neuhausen SL; Lott P; COLUMBUS Consortium; Echeverry M; Carvajal-Carmona L; Burchard E; Eng C; Long J; Zheng W; Olopade O; Huo D; Haiman C; Ziv E | January 14, 2019 | PubMed abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P?

Authors: Huyghe JR; Bien SA; Harrison TA; Kang HM; Chen S; Schmit SL; Conti DV; Qu C; Jeon J; Edlund CK; Greenside P; Wainberg M; Schumacher FR; Smith JD; Levine DM; Nelson SC; Sinnott-Armstrong NA; Albanes D; Alonso MH; Anderson K; Arnau-Collell C; Arndt V; Bamia C; Banbury BL; Baron JA; Berndt SI; Bézieau S; Bishop DT; Boehm J; Boeing H; Brenner H; Brezina S; Buch S; Buchanan DD; Burnett-Hartman A; Butterbach K; Caan BJ; Campbell PT; Carlson CS; Castellví-Bel S; Chan AT; Chang-Claude J; Chanock SJ; Chirlaque MD; Cho SH; Connolly CM; Cross AJ; Cuk K; Curtis KR; de la Chapelle A; Doheny KF; Duggan D; Easton DF; Elias SG; Elliott F; English DR; Feskens EJM; Figueiredo JC; Fischer R; FitzGerald LM; Forman D; Gala M; Gallinger S; Gauderman WJ; Giles GG; Gillanders E; Gong J; Goodman PJ; Grady WM; Grove JS; Gsur A; Gunter MJ; Haile RW; Hampe J; Hampel H; Harlid S; Hayes RB; Hofer P; Hoffmeister M; Hopper JL; Hsu WL; Huang WY; Hudson TJ; Hunter DJ; Ibañez-Sanz G; Idos GE; Ingersoll R; Jackson RD; Jacobs EJ; Jenkins MA; Joshi AD; Joshu CE; Keku TO; Key TJ; Kim HR; Kobayashi E; Kolonel LN; Kooperberg C; Kühn T; Küry S; Kweon SS; Larsson SC; Laurie CA; Le Marchand L; Leal SM; Lee SC; Lejbkowicz F; Lemire M; Li CI; Li L; Lieb W; Lin Y; Lindblom A; Lindor NM; Ling H; Louie TL; Männistö S; Markowitz SD; Martín V; Masala G; McNeil CE; Melas M; Milne RL; Moreno L; Murphy N; Myte R; Naccarati A; Newcomb PA; Offit K; Ogino S; Onland-Moret NC; Pardini B; Parfrey PS; Pearlman R; Perduca V; Pharoah PDP; Pinchev M; Platz EA; Prentice RL; Pugh E; Raskin L; Rennert G; Rennert HS; Riboli E; Rodríguez-Barranco M; Romm J; Sakoda LC; Schafmayer C; Schoen RE; Seminara D; Shah M; Shelford T; Shin MH; Shulman K; Sieri S; Slattery ML; Southey MC; Stadler ZK; Stegmaier C; Su YR; Tangen CM; Thibodeau SN; Thomas DC; Thomas SS; Toland AE; Trichopoulou A; Ulrich CM; Van Den Berg DJ; van Duijnhoven FJB; Van Guelpen B; van Kranen H; Vijai J; Visvanathan K; Vodicka P; Vodickova L; Vymetalkova V; Weigl K; Weinstein SJ; White E; Win AK; Wolf CR; Wolk A; Woods MO; Wu AH; Zaidi SH; Zanke BW; Zhang Q; Zheng W; Scacheri PC; Potter JD; Bassik MC; Kundaje A; Casey G; Moreno V; Abecasis GR; Nickerson DA; Gruber SB; Hsu L; Peters U | January 1, 2019 | PubMed abstract

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.

Authors: Chi C; Shao X; Rhead B; Gonzales E; Smith JB; Xiang AH; Graves J; Waldman A; Lotze T; Schreiner T; Weinstock-Guttman B; Aaen G; Tillema JM; Ness J; Candee M; Krupp L; Gorman M; Benson L; Chitnis T; Mar S; Belman A; Casper TC; Rose J; Moodley M; Rensel M; Rodriguez M; Greenberg B; Kahn L; Rubin J; Schaefer C; Waubant E; Langer-Gould A; Barcellos LF | January 1, 2019 | PubMed abstract

Cutaneous squamous cell cancers (cSCCs) present an under-recognized health issue among non-Hispanic whites, one that is likely to increase as populations age. cSCC risks vary considerably among non-Hispanic whites, and this heterogeneity indicates the need for risk-stratified screening strategies that are guided by patients’ personal characteristics and clinical histories. Here we describe cSCCscore, a prediction tool that uses patients’ covariates and clinical histories to assign them personal probabilities of developing cSCCs within 3 years after risk assessment. cSCCscore uses a statistical model for the occurrence and timing of a patient’s cSCCs, whose parameters we estimated using cohort data from 66,995 patients in the Kaiser Permanente Northern California healthcare system. We found that patients’ covariates and histories explained approximately 75% of their interpersonal cSCC risk variation. Using cross-validated performance measures, we also found cSCCscore’s predictions to be moderately well calibrated to the patients’ observed cSCC incidence. Moreover, cSCCscore discriminated well between patients who subsequently did and did not develop a new primary cSCC within 3 years after risk assignment, with area under the receiver operating characteristic curve of approximately 85%. Thus, cSCCscore can facilitate more informed management of non-Hispanic white patients at cSCC risk. cSCCscore’s predictions are available at https://researchapps.github.io/cSCCscore/.

Authors: Wang W; Jorgenson E; Ioannidis NM; Asgari MM; Whittemore AS | December 1, 2018 | PubMed abstract

Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive. We sought to identify and characterize functional variants in the 17q21 locus. We used the Exome Aggregation Consortium browser to identify coding (amino acid-changing) variants in the 17q21 locus. We obtained asthma association measures for these variants in both the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (16,274 cases and 38,269 matched controls) and the EVE Consortium study (5,303 asthma cases and 12,560 individuals). Gene expression and protein localization were determined by quantitative RT-PCR and fluorescence immunostaining, respectively. Molecular and cellular studies were performed to determine the functional effects of coding variants. Two coding variants (rs2305480 and rs11078928) of the gasdermin B (GSDMB) gene in the 17q21 locus were associated with lower asthma risk in both GERA (odds ratio, 0.92; P = 1.01 × 10-6) and EVE (odds ratio, 0.85; joint PEVE = 1.31 × 10-13). In GERA, rs11078928 had a minor allele frequency (MAF) of 0.45 in unaffected (nonasthmatic) controls and 0.43 in asthma cases. For European Americans in EVE, the MAF of rs2305480 was 0.45 for controls and 0.39 for cases; for all EVE subjects, the MAF was 0.32 for controls and 0.27 for cases. GSDMB is highly expressed in differentiated airway epithelial cells, including the ciliated cells. We found that, when the GSDMB protein is cleaved by inflammatory caspase-1 to release its N-terminal fragment, potent pyroptotic cell death is induced. The splice variant rs11078928 deletes the entire exon 6, which encodes 13 amino acids in the critical N-terminus, and abolishes the pyroptotic activity of the GSDMB protein. Our study identified a functional asthma variant in the GSDMB gene of the 17q21 locus and implicates GSDMB-mediated epithelial cell pyroptosis in pathogenesis.

Authors: Panganiban RA; Sun M; Dahlin A; Park HR; Kan M; Himes BE; Mitchel JA; Iribarren C; Jorgenson E; Randell SH; Israel E; Tantisira K; Shore S; Park JA; Weiss ST; Wu AC; Lu Q | November 1, 2018 | PubMed abstract

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer with genetic susceptibility loci identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) using imputed gene expression levels can identify additional gene-level associations. Here we impute gene expression levels in 6891 cSCC cases and 54,566 controls in the Kaiser Permanente Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort and 25,558 self-reported cSCC cases and 673,788 controls from 23andMe. In a discovery-validation study, we identify 19 loci containing 33 genes whose imputed expression levels are associated with cSCC at false discovery rate < 10% in the GERA cohort and validate 15 of these candidate genes at Bonferroni significance in the 23andMe dataset, including eight genes in five novel susceptibility loci and seven genes in four previously associated loci. These results suggest genetic mechanisms contributing to cSCC risk and illustrate advantages and disadvantages of TWAS as a supplement to traditional GWAS analyses.

Authors: Ioannidis NM; Wang W; Furlotte NA; Hinds DA; 23andMe Research Team; Bustamante CD; Jorgenson E; Asgari MM; Whittemore AS | October 15, 2018 | PubMed abstract

Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the discovery cohort, we identified a single locus (rs17185536-T) on chromosome 6 near the single-minded family basic helix-loop-helix transcription factor 1 (SIM1) gene that was significantly associated with the risk of erectile dysfunction (odds ratio = 1.26, P = 3.4 × 10-25). The association replicated in the UK Biobank sample (odds ratio = 1.25, P = 6.8 × 10-14), and the effect is independent of known erectile dysfunction risk factors, including body mass index (BMI). The risk locus resides on the same topologically associating domain as SIM1 and interacts with the SIM1 promoter, and the rs17185536-T risk allele showed differential enhancer activity. SIM1 is part of the leptin-melanocortin system, which has an established role in body weight homeostasis and sexual function. Because the variants associated with erectile dysfunction are not associated with differences in BMI, our findings suggest a mechanism that is specific to sexual function.

Authors: Jorgenson E; Matharu N; Palmer MR; Yin J; Shan J; Hoffmann TJ; Thai KK; Zhou X; Hotaling JM; Jarvik GP; Ahituv N; Wessells H; Van Den Eeden SK | October 1, 2018 | PubMed abstract

Body mass index (BMI), a proxy measure for obesity, is determined by both environmental (including ethnicity, age, and sex) and genetic factors, with > 400 BMI-associated loci identified to date. However, the impact, interplay, and underlying biological mechanisms among BMI, environment, genetics, and ancestry are not completely understood. To further examine these relationships, we utilized 427,509 calendar year-averaged BMI measurements from 100,418 adults from the single large multiethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We observed substantial independent ancestry and nationality differences, including ancestry principal component interactions and nonlinear effects. To increase the list of BMI-associated variants before assessing other differences, we conducted a genome-wide association study (GWAS) in GERA, with replication in the Genetic Investigation of Anthropomorphic Traits (GIANT) consortium combined with the UK Biobank (UKB), followed by GWAS in GERA combined with GIANT, with replication in the UKB. We discovered 30 novel independent BMI loci (P < 5.0 × 10-8) that replicated. We then assessed the proportion of BMI variance explained by sex in the UKB using previously identified loci compared to previously and newly identified loci and found slight increases: from 3.0 to 3.3% for males and from 2.7 to 3.0% for females. Further, the variance explained by previously and newly identified variants decreased with increasing age in the GERA and UKB cohorts, echoed in the variance explained by the entire genome, which also showed gene-age interaction effects. Finally, we conducted a tissue expression QTL enrichment analysis, which revealed that GWAS BMI-associated variants were enriched in the cerebellum, consistent with prior work in humans and mice.

Authors: Hoffmann TJ; Choquet H; Yin J; Banda Y; Kvale MN; Glymour M; Schaefer C; Risch N; Jorgenson E | October 1, 2018 | PubMed abstract

Low-density lipoprotein cholesterol (LDL-C) response to statin therapy has not been fully elucidated in real-world populations. The primary objective of this study was to characterize statin LDL-C dose-response and its heritability in a large, multiethnic population of statin users. We determined the effect of statin dosing on lipid measures utilizing electronic health records in 33 139 statin users from the Kaiser Permanente GERA cohort (Genetic Epidemiology Research on Adult Health and Aging). The relationship between statin defined daily dose and lipid parameter response (percent change) was determined. Defined daily dose and LDL-C response was associated in a log-linear relationship (β, -6.17; SE, 0.09; P<10-300) which remained significant after adjusting for prespecified covariates (adjusted β, -5.59; SE, 0.12; P<10-300). Statin type, sex, age, smoking status, diabetes mellitus, and East Asian race/ethnicity were significant independent predictors of statin-induced changes in LDL-C. Based on a variance-component method within the subset of statin users who had at least 1 first-degree relative who was also a statin user (n=1036), heritability of statin LDL-C response was estimated at 11.7% (SE, 8.6%; P=0.087). Using electronic health record data, we observed a statin LDL-C dose-response consistent with the rule of 6% from prior clinical trial data. Clinical and demographic predictors of statin LDL-C response exhibited highly significant but modest effects. Finally, statin-induced changes in LDL-C were not found to be strongly inherited. Ultimately, these findings demonstrate (1) the utility of electronic health records as a reliable source to generate robust phenotypes for pharmacogenomic research and (2) the potential role of statin precision medicine in lipid management.

Authors: Oni-Orisan A; Hoffmann TJ; Ranatunga D; Medina MW; Jorgenson E; Schaefer C; Krauss RM; Iribarren C; Risch N | September 1, 2018 | PubMed abstract

In a Policy Forum, Muin Khoury and colleagues discuss research on the clinical application of genome sequencing data.

Authors: Khoury MJ; Feero WG; Chambers DA; Brody LC; Aziz N; Green RC; Janssens ACJW; Murray MF; Rodriguez LL; Rutter JL; Schully SD; Winn DM; Mensah GA | August 1, 2018 | PubMed abstract

The immune system has been implicated in the pathophysiology of cutaneous squamous cell carcinoma (cSCC) as evidenced by the substantially increased risk of cSCC in immunosuppressed individuals. Associations between cSCC risk and single nucleotide polymorphisms (SNPs) in the HLA region have been identified by genome-wide association studies (GWAS). The translation of the associated HLA SNPs to structural amino acids changes in HLA molecules has not been previously elucidated. Using data from a GWAS that included 7238 cSCC cases and 56,961 controls of non-Hispanic white ancestry, we imputed classical alleles and corresponding amino acid changes in HLA genes. Logistic regression models were used to examine associations between cSCC risk and genotyped or imputed SNPs, classical HLA alleles, and amino acid changes. Among the genotyped SNPs, cSCC risk was associated with rs28535317 (OR = 1.20, p = 9.88 × 10- 11) corresponding to an amino-acid change from phenylalanine to leucine at codon 26 of HLA-DRB1 (OR = 1.17, p = 2.48 × 10- 10). An additional independent association was observed for a threonine to isoleucine change at codon 107 of HLA-DQA1 (OR = 1.14, p = 2.34 × 10- 9). Among the classical HLA alleles, cSCC was associated with DRB1*01 (OR = 1.18, p = 5.86 × 10- 10). Conditional analyses revealed additional independent cSCC associations with DQA1*05:01 and DQA1*05:05. Extended haplotype analysis was used to complement the imputed haplotypes, which identified three extended haplotypes in the HLA-DR and HLA-DQ regions. Associations with specific HLA-DR and -DQ alleles are likely to explain previously observed GWAS signals in the HLA region associated with cSCC risk.

Authors: Wang W; Ollila HM; Whittemore AS; Demehri S; Ioannidis NM; Jorgenson E; Mignot E; Asgari MM | July 1, 2018 | PubMed abstract

Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in United States, and its incidence is substantially higher in men than women, but the reasons for the difference are unknown. We explored whether common mitochondrial DNA (mtDNA) haplogroups, which have been associated with cancer risk, and in particular squamous cell carcinoma risk arising in other organs, could explain this biological sex difference in cSCC susceptibility.Methods: We performed a retrospective cohort study using data from the Genetic Epidemiology Research in Adult Health and Aging cohort composed of 67,868 non-Hispanic white subjects (7,701 cSCC cases and 60,167 controls). Genotype information on >665,000 SNPs was generated using Affymetrix Axiom arrays designed to maximize genome-wide coverage, and 102 high-quality mtDNA SNPs were used to determine mtDNA haplogroups. Associations between each mtDNA haplogroup and cSCC risk were evaluated by logistic regression analysis adjusting for age, sex, and population stratification using ancestry principal components.Results: cSCC was more common in men (15.4% vs. 8.4% for women). Nine common mtDNA haplogroups (frequency ≥1%) were identified in addition to the most common haplogroup, H, used as the reference group. No association with cSCC risk was detected for any of the mtDNA haplogroups or overall or sex-stratified analyses.Conclusions: Common mitochondrial variation is not associated with cSCC risk.Impact: This well-powered study refutes the hypothesis that common mitochondrial haplogroups play a role in the differential sex predilection of cSCCs. Cancer Epidemiol Biomarkers Prev; 27(7); 838-41. ©2018 AACR.

Authors: Jorgenson E; Choquet H; Yin J; Asgari MM | July 1, 2018 | PubMed abstract

Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10-8), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5-3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis.

Authors: Choquet H; Paylakhi S; Kneeland SC; Thai KK; Hoffmann TJ; Yin J; Kvale MN; Banda Y; Tolman NG; Williams PA; Schaefer C; Melles RB; Risch N; John SWM; Nair KS; Jorgenson E | June 11, 2018 | PubMed abstract

We examined the clinical utility of two multi-locus genetic risk scores (GRSs) previously validated in Europeans among persons of African (AFR; n = 2,089), Latino (LAT; n = 4,349) and East-Asian (EA; n = 4,804) ancestry. We used data from the GERA cohort (30-79 years old, 68 to 73% female). We utilized two GRSs with 12 and 51 SNPs, respectively, and the Framingham Risk Score (FRS) to estimate 10-year CHD risk. After a median 8.7 years of follow-up, 450 incident CHD events were documented (95 in AFR, 316 in LAT and 39 EA, respectively). In a model adjusting for principal components and risk factors, tertile 3 vs. tertile 1 of GRS_12 was associated with 1.86 (95% CI, 1.15-3.01), 1.52 (95% CI, 1.02-2.25) and 1.19 (95% CI, 0.77-1.83) increased hazard of CHD in AFR, LAT and EA, respectively. Inclusion of the GRSs in models containing the FRS did not increase the C-statistic but resulted in net overall reclassification of 10% of AFR, 7% LAT and EA and in reclassification of 13% of AFR and EA as well as 10% LAT in the intermediate FRS risk subset. Our results support the usefulness of incorporating genetic information into risk assessment for primary prevention among minority subjects in the U.S.

Authors: Iribarren C; Lu M; Jorgenson E; Martínez M; Lluis-Ganella C; Subirana I; Salas E; Elosua R | May 1, 2018 | PubMed abstract

Plantar fascial disorder is comprised of plantar fasciitis and plantar fibromatosis. Plantar fasciitis is the most common cause of heel pain, especially for athletes involved in running and jumping sports. Plantar fibromatosis is a rare fibrous hyperproliferation of the deep connective tissue of the foot. To identify genetic loci associated with plantar fascial disorders, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 21,624 cases of plantar fascial disorders and 80,879 controls. One indel (chr5:118704153:D) and one SNP (rs62051384) showed an association with plantar fascial disorders at genome-wide significance (p<5×10-8) with small effects (odds ratios=0.93 and 1.07 per allele, respectively). The indel chr5:118704153:D is located within TNFAIP8 (encodes a protein induced by TNF alpha) and rs62051384 is located within WWP2 (which is involved in proteasomal degradation). These DNA variants may be informative in explaining why some individuals are at higher risk for plantar fascial disorders than others.

Authors: Kim SK; Ioannidis JPA; Ahmed MA; Avins AL; Kleimeyer JP; Fredericson M; Dragoo JL | April 1, 2018 | PubMed abstract

To describe the relationship between the incidence of age-related macular degeneration (AMD) and nonsteroidal anti-inflammatory drug (NSAIDs) use. Prospective cohort study. This study consisted of participants in the California Men’s Health Study. Those who completed surveys in 2002-2003 and 2006 were included. Men who self-reported use of aspirin, ibuprofen, naproxen, valdecoxib, celecoxib, and/or rofecoxib at least 3 days per week were considered NSAID users. Patients were categorized as non-users, former users, new users, or longer-term users based on survey responses. NSAID use was also categorized by type: any NSAIDs, aspirin, and/or non-aspirin NSAIDs. Age, race/ethnicity, smoking status, education, income, alcohol use, and Charlson comorbidity index score were included in the multivariate analysis as risk factors for AMD. A total of 51 371 men were included. Average follow-up time was 7.4 years. There were 292 (0.6%) and 1536 (3%) cases of exudative and nonexudative AMD, respectively. Longer-term use of any NSAID was associated with lower risk of exudative AMD (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.50-0.96, P = .029). New users of any NSAIDs (HR = 0.79, 95% CI 0.68-0.93, P = .0039) and aspirin (HR = 0.82, 95% CI 0.70-0.97, P = .018) had a lower risk of nonexudative AMD, although this trend did not persist in longer-term users. The relationship between exudative or nonexudative AMD and the remaining categories of NSAID use were not significant. The overall impact of NSAIDs on AMD incidence is small; however, the lower risk of exudative AMD in longer-term NSAID users may point to a protective effect and deserves further study as a possible mechanism to modulate disease risk.

Authors: Modjtahedi BS; Fong DS; Jorgenson E; Van Den Eeden SK; Quinn V; Slezak JM | April 1, 2018 | PubMed abstract

Genome-wide association studies have identified genetic loci associated with cutaneous squamous cell carcinoma (cSCC) risk, but single-nucleotide polymorphism associations with cSCC invasiveness have not been investigated. We examined associations between cSCC invasiveness and 23 reported single-nucleotide polymorphisms among 67,833 non-Hispanic white subjects. Additionally, we performed a genome-wide scan and identified one SNP with significantly different frequencies in 5,724 subjects with at least one invasive tumor and 1,943 subjects with in situ tumors only. We then compared genotype frequencies among the invasive and in situ groups with those of 60,166 control subjects. The genome-wide scan identified that the T allele in single-nucleotide polymorphism rs41269979 in the class II human leukocyte antigen region was more frequent in the invasive than the in situ group (P = 4.93 × 10-8). Single-nucleotide polymorphisms in five of the 23 previously associated loci showed odds ratio heterogeneity between the in situ and invasive groups: rs447510 in HLA-DQA1 (Phet = 2.93 × 10-3), rs12203592 in IRF4 (Phet = 3.94 × 10-4), rs1805007 in MC1R (Phet = 7.71 × 10-3), and two SNPs in DEF8 (rs4268748, Phet = 1.09 × 10-4 and rs8063761, Phet = 1.40 × 10-4). These findings may provide new insight into the genetic basis of cSCC invasiveness and may help identify individuals at higher risk for developing clinically aggressive cSCC.

Authors: Wang W; Jorgenson E; Whittemore AS; Asgari MM | March 1, 2018 | PubMed abstract

A genome-wide association study (GWAS) of 94,674 ancestrally diverse Kaiser Permanente members using 478,866 longitudinal electronic health record (EHR)-derived measurements for untreated serum lipid levels empowered multiple new findings: 121 new SNP associations (46 primary, 15 conditional, and 60 in meta-analysis with Global Lipids Genetic Consortium data); an increase of 33-42% in variance explained with multiple measurements; sex differences in genetic impact (greater impact in females for LDL, HDL, and total cholesterol and the opposite for triglycerides); differences in variance explained among non-Hispanic whites, Latinos, African Americans, and East Asians; genetic dominance and epistatic interaction, with strong evidence for both at the ABO and FUT2 genes for LDL; and tissue-specific enrichment of GWAS-associated SNPs among liver, adipose, and pancreas eQTLs. Using EHR pharmacy data, both LDL and triglyceride genetic risk scores (477 SNPs) were strongly predictive of age at initiation of lipid-lowering treatment. These findings highlight the value of longitudinal EHRs for identifying new genetic features of cholesterol and lipoprotein metabolism with implications for lipid treatment and risk of coronary heart disease.

Authors: Hoffmann TJ; Theusch E; Haldar T; Ranatunga DK; Jorgenson E; Medina MW; Kvale MN; Kwok PY; Schaefer C; Krauss RM; Iribarren C; Risch N | March 1, 2018 | PubMed abstract

Elevated lipoprotein(a) levels are a risk factor for aortic stenosis (AS). However, a large-scale replication of associations between LPA variants and AS, their interactions with risk factors, and the effect of multiple risk alleles is not well established. To replicate the association between LPA variants with AS and identify subgroups who are at higher risk of developing AS. This case-control study of AS included 44 703 individuals (3469 cases) 55 years or older who were enrolled in the Genetic Epidemiology Research on Aging cohort and who were members of the Kaiser Permanente Northern California health care delivery system. The study leveraged the linkage of administrative health data, electronic medical records, genotypes, and self-reported questionnaire data. The 3469 AS cases were diagnosed between January 1996 and December 2015. Individuals with congential valvular heart disease were excluded. Two single-nucleotide polymorphisms in the LPA locus, rs10455872 and rs3798220, that are known to associate with circulating plasma lipoprotein(a) levels and an LPA risk score. Aortic stenosis or aortic valve replacement. The 44 703 participants were of European ancestry,of whom 22 019 (49.3%) were men. The mean (SD) age for the control group was 69.3 (8.3) years and the mean (SD) age for AS cases was 74.6 (8.5) years. Both LPA variants were associated with AS, with a per risk allele odds ratio of 1.34 (95% CI, 1.23-1.47; P = 1.7 × 10-10) for rs10455872 and 1.31 (95% CI, 1.09-1.58; P = 3.6 × 10-3) for rs3798220 after adjusting for age, age2, and sex. The results remained significant after adjusting for risk factors. The estimates were similar for an LPA risk score. Individuals with 2 risk alleles had a 2-fold or greater odds of AS compared with individuals with no risk alleles (for rs10455872, homozygous odds ratio, 2.05; 95% CI, 1.37-3.07; P = 5.3 × 10-4; for rs3798220, homozygous odds ratio, 3.74; 95% CI, 1.03-13.62; P = .05; and for compound heterygotes, odds ratio, 2.00; 95% CI, 1.17-3.44; P = .01). For rs10455872, the odds ratio for AS was greatest in individuals aged 55 to 64 years and declined with age (interaction P = .03). Each rs10455872 risk allele was also associated with AS that was diagnosed 0.71 years earlier (95% CI, -1.42 to 0; P = .05). We provide a large-scale confirmation of the association between 2 LPA variants and AS, reaching genome-wide significance. In addition, individuals with 2 risk alleles have 2-fold or greater odds of developing AS. Age may modify these associations and identify subgroups who are at greater risk of developing AS.

Authors: Chen HY; Dufresne L; Burr H; Ambikkumar A; Yasui N; Luk K; Ranatunga DK; Whitmer RA; Lathrop M; Engert JC; Thanassoulis G | January 1, 2018 | PubMed abstract

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, a leading cause of blindness. IOP heritability has been estimated to up to 67%, and to date only 11 IOP loci have been reported, accounting for 1.5% of IOP variability. Here, we conduct a genome-wide association study of IOP in 69,756 untreated individuals of European, Latino, Asian, and African ancestry. Multiple longitudinal IOP measurements were collected through electronic health records and, in total, 356,987 measurements were included. We identify 47 genome-wide significant IOP-associated loci (P < 5 × 10-8); of the 40 novel loci, 14 replicate at Bonferroni significance in an external genome-wide association study analysis of 37,930 individuals of European and Asian descent. We further examine their effect on the risk of glaucoma within our discovery sample. Using longitudinal IOP measurements from electronic health records improves our power to identify new variants, which together explain 3.7% of IOP variation.

Authors: Choquet H; Thai KK; Yin J; Hoffmann TJ; Kvale MN; Banda Y; Schaefer C; Risch N; Nair KS; Melles R; Jorgenson E | December 13, 2017 | PubMed abstract

Rotator cuff tears are common, especially in the fifth and sixth decades of life, but can also occur in the competitive athlete. Genetic differences may contribute to overall injury risk. Identifying genetic loci associated with rotator cuff injury could shed light on the etiology of this injury. We performed a genome-wide association screen using publically available data from the Research Program in Genes, Environment and Health including 8,357 cases of rotator cuff injury and 94,622 controls. We found rs71404070 to show a genome-wide significant association with rotator cuff injury with p = 2.31×10-8 and an odds ratio of 1.25 per allele. This SNP is located next to cadherin8, which encodes a protein involved in cell adhesion. We also attempted to validate previous gene association studies that had reported a total of 18 SNPs showing a significant association with rotator cuff injury. However, none of the 18 SNPs were validated in our dataset. rs71404070 may be informative in explaining why some individuals are more susceptible to rotator cuff injury than others.

Authors: Roos TR; Roos AK; Avins AL; Ahmed MA; Kleimeyer JP; Fredericson M; Ioannidis JPA; Dragoo JL; Kim SK | December 12, 2017 | PubMed abstract

De Quervain’s tenosynovitis is a repetitive strain injury involving synovial inflammation of the tendons of the first extensor compartment of the wrist. It is relatively common in the general population, and is the most common radial-sided tendinopathy seen in athletes. Identifying a genetic marker associated with de Quervain’s tenosynovitis could provide a useful tool to help identify those individuals with an increased risk for injury. A genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health (RPGEH) including 4,129 cases and 98,374 controls. rs35360670 on chromosome 8 showed an association with de Quervain’s tenosynovitis at genome-wide significance (p=1.9×10-8; OR=1.46; 95% CI=1.38-1.59). This study is the first genome-wide screen for de Quervain’s tenosynovitis and provides insights regarding its genetic etiology as well as a DNA marker with the potential to inform athletes and other high-risk individuals about their relative risk for injury.

Authors: Kim SK; Ahmed MA; Avins AL; Ioannidis JPA | November 1, 2017 | PubMed abstract

Ankle injuries, including sprains, strains and other joint derangements and instability, are common, especially for athletes involved in indoor court or jumping sports. Identifying genetic loci associated with these ankle injuries could shed light on their etiologies. A genome-wide association screen was performed using publicly available data from the Research Program in Genes, Environment and Health (RPGEH) including 1,694 cases of ankle injury and 97,646 controls. An indel (chr21:47156779:D) that lies close to a collagen gene, COL18A1, showed an association with ankle injury at genome-wide significance (p = 3.8×10-8; OR = 1.99; 95% CI = 1.75-2.23). A second DNA variant (rs13286037 on chromosome 9) that lies within an intron of the transcription factor gene NFIB showed an association that was nearly genome-wide significant (p = 5.1×10-8; OR = 1.63; 95% CI = 1.46-1.80). The ACTN3 R577X mutation was previously reported to show an association with acute ankle sprains, but did not show an association in this cohort. This study is the first genome-wide screen for ankle injury that yields insights regarding the genetic etiology of ankle injuries and provides DNA markers with the potential to inform athletes about their genetic risk for ankle injury.

Authors: Kim SK; Kleimeyer JP; Ahmed MA; Avins AL; Fredericson M; Dragoo JL; Ioannidis JPA | September 29, 2017 | PubMed abstract

Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic whites, Hispanic/Latinos, East Asians and African Americans. We examined two statistically independent phenotypes reflecting subjects’ alcohol consumption during the past year, based on self-reported information: any alcohol intake (drinker/non-drinker status) and the regular quantity of drinks consumed per week (drinks/week) among drinkers. We assessed these two alcohol consumption phenotypes in each race/ethnicity group, and in a combined trans-ethnic meta-analysis comprising a total of 86 627 individuals. We observed the strongest association between the previously reported single nucleotide polymorphism (SNP) rs671 in ALDH2 and alcohol drinker status (odd ratio (OR)=0.40, P=2.28 × 10-72) in East Asians, and also an effect on drinks/week (beta=-0.17, P=5.42 × 10-4) in the same group. We also observed a genome-wide significant association in non-Hispanic whites between the previously reported SNP rs1229984 in ADH1B and both alcohol consumption phenotypes (OR=0.79, P=2.47 × 10-20for drinker status and beta=-0.19, P=1.91 × 10-35for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, P=4.35 × 10-7and beta=-0.21, P=2.58 × 10-6, respectively). Although prior studies reported effects of ADH1B and ALDH2 on lifetime measures, such as risk of alcohol dependence, our study adds further evidence of the effect of the same genes on a cross-sectional measure of average drinking. Our trans-ethnic meta-analysis confirmed recent findings implicating the KLB and GCKR loci in alcohol consumption, with strongest associations observed for rs7686419 (beta=-0.04, P=3.41 × 10-10for drinks/week and OR=0.96, P=4.08 × 10-5for drinker status), and rs4665985 (beta=0.04, P=2.26 × 10-8for drinks/week and OR=1.04, P=5 × 10-4for drinker status), respectively. Finally, we also obtained confirmatory results extending previous findings implicating AUTS2, SGOL1 and SERPINC1 genes in alcohol consumption traits in non-Hispanic whites.

Authors: Jorgenson E; Thai KK; Hoffmann TJ; Sakoda LC; Kvale MN; Banda Y; Schaefer C; Risch N; Mertens J; Weisner C; Choquet H | September 1, 2017 | PubMed abstract

Medial collateral ligament (MCL) injuries are a common knee injury, especially in competitive athletes. Identifying genetic loci associated with MCL injury could shed light on its etiology. A genome-wide association screen was performed using data from the Research Program in Genes, Environment and Health (RPGEH) including 1 572 cases of MCL injury and 100 931 controls. 2 SNPs (rs80351309 and rs6083471) showed an association with MCL injury at genome-wide significance (p<5×10-8) with moderate effects (odds ratios=2.12 and 1.57, respectively). For rs80351309, the genotypes were imputed with only moderate accuracy, so this SNP should be viewed with caution until its association with MCL injury can be validated. The SNPs rs80351309 and rs6083471 show a statistically significant association with MCL injury. It will be important to replicate this finding in future studies.

Authors: Roos AK; Avins AL; Ahmed MA; Kleimeyer JP; Roos TR; Fredericson M; Ioannidis JPA; Dragoo JL; Kim S | July 1, 2017 | PubMed abstract

Shoulder dislocations are common shoulder injuries associated with athletic activity in contact sports, such as football, rugby, wrestling, and hockey. Identifying genetic loci associated with shoulder dislocation could shed light on underlying mechanisms for injury and identify predictive genetic markers. To identify DNA polymorphisms associated with shoulder dislocation, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 662 cases of shoulder dislocation and 82 602 controls from the European ancestry group. rs12913965 showed an association with shoulder dislocation at genome-wide significance (p=9.7×10-9; odds ratio=1.6) from the European ancestry group. Individuals carrying one copy of the risk allele (T) at rs12913965 showed a 69% increased risk for shoulder dislocation in our cohort. rs12913965 is located within an intron of the TICRR gene, which encodes TOPBP1 interacting checkpoint and replication regulator involved in the cell cycle. rs12913965 is also associated with changes in expression of the ISG20 gene, which encodes an antiviral nuclease induced by interferons. This genetic marker may one day be used to identify athletes with a higher genetic risk for shoulder dislocation. It will be important to replicate this finding in future studies.

Authors: Kim S; Kleimeyer JP; Ahmed MA; Avins AL; Fredericson M; Dragoo JL; Ioannidis JPA | July 1, 2017 | PubMed abstract

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Authors: Dujic T; Zhou K; Yee SW; van Leeuwen N; de Keyser CE; Javorský M; Goswami S; Zaharenko L; Hougaard Christensen MM; Out M; Tavendale R; Kubo M; Hedderson MM; van der Heijden AA; Klimčáková L; Pirags V; Kooy A; Brøsen K; Klovins J; Semiz S; Tkáč I; Stricker BH; Palmer C; 't Hart LM; Giacomini KM; Pearson ER | June 1, 2017 | PubMed abstract

To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS). We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820). Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model. We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.

Authors: Gianfrancesco MA; Stridh P; Rhead B; Shao X; Xu E; Graves JS; Chitnis T; Waldman A; Lotze T; Schreiner T; Belman A; Greenberg B; Weinstock-Guttman B; Aaen G; Tillema JM; Hart J; Caillier S; Ness J; Harris Y; Rubin J; Candee M; Krupp L; Gorman M; Benson L; Rodriguez M; Mar S; Kahn I; Rose J; Roalstad S; Casper TC; Shen L; Quach H; Quach D; Hillert J; Bäärnhielm M; Hedstrom A; Olsson T; Kockum I; Alfredsson L; Metayer C; Schaefer C; Barcellos LF; Waubant E; Network of Pediatric Multiple Sclerosis Centers | April 25, 2017 | PubMed abstract

Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.

Authors: Gianfrancesco MA; Glymour MM; Walter S; Rhead B; Shao X; Shen L; Quach H; Hubbard A; Jónsdóttir I; Stefánsson K; Strid P; Hillert J; Hedström A; Olsson T; Kockum I; Schaefer C; Alfredsson L; Barcellos LF | February 1, 2017 | PubMed abstract

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa-such as genetics-can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

Authors: Hoffmann TJ; Passarelli MN; Graff RE; Emami NC; Sakoda LC; Jorgenson E; Habel LA; Shan J; Ranatunga DK; Quesenberry CP; Chao CR; Ghai NR; Aaronson D; Presti J; Nordström T; Wang Z; Berndt SI; Chanock SJ; Mosley JD; Klein RJ; Middha M; Lilja H; Melander O; Kvale MN; Kwok PY; Schaefer C; Risch N; Van Den Eeden SK; Witte JS | January 31, 2017 | PubMed abstract

The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Authors: Brant SR; Okou DT; Simpson CL; Cutler DJ; Haritunians T; Bradfield JP; Chopra P; Prince J; Begum F; Kumar A; Huang C; Venkateswaran S; Datta LW; Wei Z; Thomas K; Herrinton LJ; Klapproth JA; Quiros AJ; Seminerio J; Liu Z; Alexander JS; Baldassano RN; Dudley-Brown S; Cross RK; Dassopoulos T; Denson LA; Dhere TA; Dryden GW; Hanson JS; Hou JK; Hussain SZ; Hyams JS; Isaacs KL; Kader H; Kappelman MD; Katz J; Kellermayer R; Kirschner BS; Kuemmerle JF; Kwon JH; Lazarev M; Li E; Mack D; Mannon P; Moulton DE; Newberry RD; Osuntokun BO; Patel AS; Saeed SA; Targan SR; Valentine JF; Wang MH; Zonca M; Rioux JD; Duerr RH; Silverberg MS; Cho JH; Hakonarson H; Zwick ME; McGovern DP; Kugathasan S | January 1, 2017 | PubMed abstract

Achilles tendinopathy or rupture and anterior cruciate ligament (ACL) rupture are substantial injuries affecting athletes, associated with delayed recovery or inability to return to competition. To identify genetic markers that might be used to predict risk for these injuries, we performed genome-wide association screens for these injuries using data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort consisting of 102,979 individuals. We did not find any single nucleotide polymorphisms (SNPs) associated with either of these injuries with a p-value that was genome-wide significant (p<5x10-8). We found, however, four and three polymorphisms with p-values that were borderline significant (p<10-6) for Achilles tendon injury and ACL rupture, respectively. We then tested SNPs previously reported to be associated with either Achilles tendon injury or ACL rupture. None showed an association in our cohort with a false discovery rate of less than 5%. We obtained, however, moderate to weak evidence for replication in one case; specifically, rs4919510 in MIR608 had a p-value of 5.1x10-3 for association with Achilles tendon injury, corresponding to a 7% chance of false replication. Finally, we tested 2855 SNPs in 90 candidate genes for musculoskeletal injury, but did not find any that showed a significant association below a false discovery rate of 5%. We provide data containing summary statistics for the entire genome, which will be useful for future genetic studies on these injuries.

Authors: Kim SK; Roos TR; Roos AK; Kleimeyer JP; Ahmed MA; Goodlin GT; Fredericson M; Ioannidis JP; Avins AL; Dragoo JL | January 1, 2017 | PubMed abstract

Longitudinal electronic health records on 99,785 Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort individuals provided 1,342,814 systolic and diastolic blood pressure measurements for a genome-wide association study on long-term average systolic, diastolic, and pulse pressure. We identified 39 new loci among 75 genome-wide significant loci (P ≤ 5 × 10(-8)), with most replicating in the combined International Consortium for Blood Pressure (ICBP; n = 69,396) and UK Biobank (UKB; n = 152,081) studies. Combining GERA with ICBP yielded 36 additional new loci, with most replicating in UKB. Combining all three studies (n = 321,262) yielded 241 additional genome-wide significant loci, although no replication sample was available for these. All associated loci explained 2.9%, 2.5%, and 3.1% of variation in systolic, diastolic, and pulse pressure, respectively, in GERA non-Hispanic whites. Using multiple blood pressure measurements in GERA doubled the variance explained. A normalized risk score was associated with time to onset of hypertension (hazards ratio = 1.18, P = 8.2 × 10(-45)). Expression quantitative trait locus analysis of blood pressure loci showed enrichment in aorta and tibial artery.

Authors: Hoffmann TJ; Ehret GB; Nandakumar P; Ranatunga D; Schaefer C; Kwok PY; Iribarren C; Chakravarti A; Risch N | January 1, 2017 | PubMed abstract

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

Authors: Barban N; Jansen R; de Vlaming R; Vaez A; Mandemakers JJ; Tropf FC; Shen X; Wilson JF; Chasman DI; Nolte IM; Tragante V; van der Laan SW; Perry JR; Kong A; BIOS Consortium; Ahluwalia TS; Albrecht E; Yerges-Armstrong L; Atzmon G; Auro K; Ayers K; Bakshi A; Ben-Avraham D; Berger K; Bergman A; Bertram L; Bielak LF; Bjornsdottir G; Bonder MJ; Broer L; Bui M; Barbieri C; Cavadino A; Chavarro JE; Turman C; Concas MP; Cordell HJ; Davies G; Eibich P; Eriksson N; Esko T; Eriksson J; Falahi F; Felix JF; Fontana MA; Franke L; Gandin I; Gaskins AJ; Gieger C; Gunderson EP; Guo X; Hayward C; He C; Hofer E; Huang H; Joshi PK; Kanoni S; Karlsson R; Kiechl S; Kifley A; Kluttig A; Kraft P; Lagou V; Lecoeur C; Lahti J; Li-Gao R; Lind PA; Liu T; Makalic E; Mamasoula C; Matteson L; Mbarek H; McArdle PF; McMahon G; Meddens SF; Mihailov E; Miller M; Missmer SA; Monnereau C; van der Most PJ; Myhre R; Nalls MA; Nutile T; Kalafati IP; Porcu E; Prokopenko I; Rajan KB; Rich-Edwards J; Rietveld CA; Robino A; Rose LM; Rueedi R; Ryan KA; Saba Y; Schmidt D; Smith JA; Stolk L; Streeten E; Tönjes A; Thorleifsson G; Ulivi S; Wedenoja J; Wellmann J; Willeit P; Yao J; Yengo L; Zhao JH; Zhao W; Zhernakova DV; Amin N; Andrews H; Balkau B; Barzilai N; Bergmann S; Biino G; Bisgaard H; Bønnelykke K; Boomsma DI; Buring JE; Campbell H; Cappellani S; Ciullo M; Cox SR; Cucca F; Toniolo D; Davey-Smith G; Deary IJ; Dedoussis G; Deloukas P; van Duijn CM; de Geus EJ; Eriksson JG; Evans DA; Faul JD; Sala CF; Froguel P; Gasparini P; Girotto G; Grabe HJ; Greiser KH; Groenen PJ; de Haan HG; Haerting J; Harris TB; Heath AC; Heikkilä K; Hofman A; Homuth G; Holliday EG; Hopper J; Hyppönen E; Jacobsson B; Jaddoe VW; Johannesson M; Jugessur A; Kähönen M; Kajantie E; Kardia SL; Keavney B; Kolcic I; Koponen P; Kovacs P; Kronenberg F; Kutalik Z; La Bianca M; Lachance G; Iacono WG; Lai S; Lehtimäki T; Liewald DC; LifeLines Cohort Study; Lindgren CM; Liu Y; Luben R; Lucht M; Luoto R; Magnus P; Magnusson PK; Martin NG; McGue M; McQuillan R; Medland SE; Meisinger C; Mellström D; Metspalu A; Traglia M; Milani L; Mitchell P; Montgomery GW; Mook-Kanamori D; de Mutsert R; Nohr EA; Ohlsson C; Olsen J; Ong KK; Paternoster L; Pattie A; Penninx BW; Perola M; Peyser PA; Pirastu M; Polasek O; Power C; Kaprio J; Raffel LJ; Räikkönen K; Raitakari O; Ridker PM; Ring SM; Roll K; Rudan I; Ruggiero D; Rujescu D; Salomaa V; Schlessinger D; Schmidt H; Schmidt R; Schupf N; Smit J; Sorice R; Spector TD; Starr JM; Stöckl D; Strauch K; Stumvoll M; Swertz MA; Thorsteinsdottir U; Thurik AR; Timpson NJ; Tung JY; Uitterlinden AG; Vaccargiu S; Viikari J; Vitart V; Völzke H; Vollenweider P; Vuckovic D; Waage J; Wagner GG; Wang JJ; Wareham NJ; Weir DR; Willemsen G; Willeit J; Wright AF; Zondervan KT; Stefansson K; Krueger RF; Lee JJ; Benjamin DJ; Cesarini D; Koellinger PD; den Hoed M; Snieder H; Mills MC | December 1, 2016 | PubMed abstract

We evaluated whether including multilocus genetic risk scores (GRSs) into the Framingham Risk Equation improves the predictive capacity, discrimination, and reclassification of asymptomatic individuals with respect to coronary heart disease (CHD) risk. We performed a cohort study among 51 954 European-ancestry members of a Northern California integrated healthcare system (67% female; mean age 59) free of CHD at baseline (2007-2008). Four GRSs were constructed using between 8 and 51 previously identified genetic variants. After a mean (±SD) follow-up of 5.9 (±1.5) years, 1864 incident CHD events were documented. All GRSs were linearly associated with CHD in a model adjusted by individual risk factors: hazard ratio (95% confidence interval) per SD unit: 1.21 (1.15-1.26) for GRS_8, 1.20 (1.15-1.26) for GRS_12, 1.23 (1.17-1.28) for GRS_36, and 1.23 (1.17-1.28) for GRS_51. Inclusion of the GRSs improved the C statistic (ΔC statistic =0.008 for GRS_8 and GRS_36; 0.007 for GRS_12; and 0.009 for GRS_51; all P<0.001). The net reclassification improvement was 5% for GRS_8, GRS_12, and GRS_36 and 4% for GRS_51 in the entire cohort and was (after correcting for bias) 9% for GRS_8 and GRS_12 and 7% for GRS_36 and GRS_51 when analyzing those classified as intermediate Framingham risk (10%-20%). The number required to treat to prevent 1 CHD after selectively treating with statins up-reclassified subjects on the basis of genetic information was 36 for GRS_8 and GRS_12, 41 for GRS_36, and 43 for GRS_51. Our results demonstrate significant and clinically relevant incremental discriminative/predictive capability of 4 multilocus GRSs for incident CHD among subjects of European ancestry.

Authors: Iribarren C; Lu M; Jorgenson E; Martínez M; Lluis-Ganella C; Subirana I; Salas E; Elosua R | December 1, 2016 | PubMed abstract

Exposures during the prenatal period may have lasting effects on maternal and child health outcomes. To better understand the effects of the in utero environment on children’s short- and long-term health, large representative pregnancy cohorts with comprehensive information on a broad range of environmental influences (including biological and behavioral) and the ability to link to prenatal, child and maternal health outcomes are needed. The Research Program on Genes, Environment and Health (RPGEH) pregnancy cohort at Kaiser Permanente Northern California (KPNC) was established to create a resource for conducting research to better understand factors influencing women’s and children’s health. Recruitment is integrated into routine clinical prenatal care at KPNC, an integrated health care delivery system. We detail the study design, data collection, and methodologies for establishing this cohort. We also describe the baseline characteristics and the cohort’s representativeness of the underlying pregnant population in KPNC. While recruitment is ongoing, as of October 2014, the RPGEH pregnancy cohort included 16,977 pregnancies (53 % from racial and ethnic minorities). RPGEH pregnancy cohort participants consented to have blood samples obtained in the first trimester (mean gestational age 9.1 weeks ± 4.2 SD) and second trimester (mean gestational age 18.1 weeks ± 5.5 SD) to be stored for future use. Women were invited to complete a questionnaire on health history and lifestyle. Information on women’s clinical and health assessments before, during and after pregnancy and women and children’s health outcomes are available in the health system’s electronic health records, which also allows long-term follow-up. This large, racially- and ethnically-diverse cohort of pregnancies with prenatal biospecimens and clinical data is a valuable resource for future studies on in utero environmental exposures and maternal and child perinatal and long term health outcomes. The baseline characteristics of RPGEH Pregnancy Cohort demonstrate that it is highly representative of the underlying population living in the broader community in Northern California.

Authors: Hedderson MM; Ferrara A; Avalos LA; Van den Eeden SK; Gunderson EP; Li DK; Altschuler A; Woo S; Rowell S; Choudhary V; Xu F; Flanagan T; Schaefer C; Croen LA | November 29, 2016 | PubMed abstract

One-third of type-2 diabetic patients respond poorly to metformin. Despite extensive research, the impact of genetic and nongenetic factors on long-term outcome is unknown. In this study we combine nonlinear mixed effect modeling with computational genetic methodologies to identify predictors of long-term response. In all, 1,056 patients contributed their genetic, demographic, and long-term HbA1c data. The top nine variants (of 12,000 variants in 267 candidate genes) accounted for approximately one-third of the variability in the disease progression parameter. Average serum creatinine level, age, and weight were determinants of symptomatic response; however, explaining negligible variability. Two single nucleotide polymorphisms (SNPs) in CSMD1 gene (rs2617102, rs2954625) and one SNP in a pharmacologically relevant SLC22A2 gene (rs316009) influenced disease progression, with minor alleles leading to less and more favorable outcomes, respectively. Overall, our study highlights the influence of genetic factors on long-term HbA1c response and provides a computational model, which when validated, may be used to individualize treatment.

Authors: Goswami S; Yee SW; Xu F; Sridhar SB; Mosley JD; Takahashi A; Kubo M; Maeda S; Davis RL; Roden DM; Hedderson MM; Giacomini KM; Savic RM | November 1, 2016 | PubMed abstract

Authors: Whittemore AS; Wang W; Jorgenson E; Asgari MM | November 1, 2016 | PubMed abstract

We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality. We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles. Findings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64-0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76-0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76-0.94). No association was observed for age at onset or disease severity. These results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors.

Authors: Rhead B; Bäärnhielm M; Gianfrancesco M; Mok A; Shao X; Quach H; Shen L; Schaefer C; Link J; Gyllenberg A; Hedström AK; Olsson T; Hillert J; Kockum I; Glymour MM; Alfredsson L; Barcellos LF | October 1, 2016 | PubMed abstract

Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.185, p = 4.0×10-11), 52Kb 3′ of ISG20, which replicated in a meta-analysis of the other GERA race/ethnicity groups (1,025 cases, 12,388 controls, p = 0.00094) and in a UK Biobank case-control analysis (30,802 self-reported cases, 78,586 controls, p = 0.015); and rs58389158 (odds ratio = 1.132, p = 1.8×10-9), which replicated in the UK Biobank (p = 0.00021). The latter SNP lies just outside exon 8 and is highly correlated (r2 = 0.96) with the missense SNP rs5756795 in exon 7 of TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. We further tested these SNPs in phenotypes from audiologist notes available on a subset of GERA (4,903 individuals), stratified by case/control status, to construct an independent replication test, and found a significant effect of rs58389158 on speech reception threshold (SRT; overall GERA meta-analysis p = 1.9×10-6). We also tested variants within exons of 132 other previously-identified hearing loss genes, and identified two common additional significant SNPs: rs2877561 (synonymous change in ILDR1, p = 6.2×10-5), which replicated in the UK Biobank (p = 0.00057), and had a significant GERA SRT (p = 0.00019) and speech discrimination score (SDS; p = 0.0019); and rs9493627 (missense change in EYA4, p = 0.00011) which replicated in the UK Biobank (p = 0.0095), other GERA groups (p = 0.0080), and had a consistent significant result for SRT (p = 0.041) and suggestive result for SDS (p = 0.081). Large cohorts with GWAS data and electronic health records may be a useful method to characterize the genetic architecture of ARHI.

Authors: Hoffmann TJ; Keats BJ; Yoshikawa N; Schaefer C; Risch N; Lustig LR | October 1, 2016 | PubMed abstract

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Authors: Zhou K; Yee SW; Seiser EL; van Leeuwen N; Tavendale R; Bennett AJ; Groves CJ; Coleman RL; van der Heijden AA; Beulens JW; de Keyser CE; Zaharenko L; Rotroff DM; Out M; Jablonski KA; Chen L; Javorský M; Židzik J; Levin AM; Williams LK; Dujic T; Semiz S; Kubo M; Chien HC; Maeda S; Witte JS; Wu L; Tkáč I; Kooy A; van Schaik RHN; Stehouwer CDA; Logie L; MetGen Investigators; DPP Investigators; ACCORD Investigators; Sutherland C; Klovins J; Pirags V; Hofman A; Stricker BH; Motsinger-Reif AA; Wagner MJ; Innocenti F; 't Hart LM; Holman RR; McCarthy MI; Hedderson MM; Palmer CNA; Florez JC; Giacomini KM; Pearson ER | September 1, 2016 | PubMed abstract

Self-reported weight prior to pregnancy is prone to error. We utilised a measured pre-conceptional weight from the electronic health record (EHR) to investigate error in recalled pre-pregnancy body mass index (BMI) category and compared how associations between pre-pregnancy BMI and pregnancy outcomes varied by using the two measures. We assessed differences in means, correlations, and categorisation of pre-pregnancy BMI for 5092 singleton pregnancies delivered between 2007 and 2013 in Kaiser Permanente Northern California. Associations between measured and self-reported BMI category and gestational diabetes, infant size for gestational age, and exceeding the Institute of Medicine gestational weight gain recommendations were assessed. Overall, the two measures assigned the same BMI category for 86.7% of women with higher risks of misclassification for overweight (Relative Risk (RR) 3.38, 95% Confidence Interval (CI) 2.79, 4.10), obese class I (RR 3.81, 95% CI 3.07, 4.75), and obese class II (RR 1.80, 95% CI 1.28, 2.55) women compared to normal weight women. However, associations between self-reported or measured BMI category and several pregnancy outcomes were similar. Despite misclassification, self-reported and measured pre-pregnancy weights were similarly associated with perinatal outcomes in this study population. Our results illustrate the value of the EHR for recording measured pre-pregnancy weight for use in research.

Authors: Han E; Abrams B; Sridhar S; Xu F; Hedderson M | July 1, 2016 | PubMed abstract

Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23 790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR)=1.21; P=1.4 × 10(-11)) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR=1.22; P=3.9 × 10(-10)) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR=1.28; P=1.30 × 10(-3), DQB1*02: OR=1.32; P=9.00 × 10(-4)). These findings support a role of HLA class II alleles in the risk of AMD.

Authors: Jorgenson E; Melles RB; Hoffmann TJ; Jia X; Sakoda LC; Kvale MN; Banda Y; Schaefer C; Risch N; Shen L | July 1, 2016 | PubMed abstract

Full-field digital mammography (FFDM) has largely replaced film-screen mammography in the US. Breast density assessed from film mammograms is strongly associated with breast cancer risk, but data are limited for processed FFDM images used for clinical care. We conducted a case-control study nested among non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were aged 40 to 74 years and had screening mammograms acquired on Hologic FFDM machines. Cases (n = 297) were women with a first invasive breast cancer diagnosed after a screening FFDM. For each case, up to five controls (n = 1149) were selected, matched on age and year of FFDM and image batch number, and who were still under follow-up and without a history of breast cancer at the age of diagnosis of the matched case. Percent density (PD) and dense area (DA) were assessed by a radiological technologist using Cumulus. Conditional logistic regression was used to estimate odds ratios (ORs) for breast cancer associated with PD and DA, modeled continuously in standard deviation (SD) increments and categorically in quintiles, after adjusting for body mass index, parity, first-degree family history of breast cancer, breast area, and menopausal hormone use. Median intra-reader reproducibility was high with a Pearson’s r of 0.956 (range 0.902 to 0.983) for replicate PD measurements across 23 image batches. The overall mean was 20.02 (SD, 14.61) for PD and 27.63 cm(2) (18.22 cm(2)) for DA. The adjusted ORs for breast cancer associated with each SD increment were 1.70 (95 % confidence interval, 1.41-2.04) for PD, and 1.54 (1.34-1.77) for DA. The adjusted ORs for each quintile were: 1.00 (ref.), 1.49 (0.91-2.45), 2.57 (1.54-4.30), 3.22 (1.91-5.43), 4.88 (2.78-8.55) for PD, and 1.00 (ref.), 1.43 (0.85-2.40), 2.53 (1.53-4.19), 2.85 (1.73-4.69), 3.48 (2.14-5.65) for DA. PD and DA measured using Cumulus on processed FFDM images are positively associated with breast cancer risk, with similar magnitudes of association as previously reported for film-screen mammograms. Processed digital mammograms acquired for routine clinical care in a general practice setting are suitable for breast density and cancer research.

Authors: Habel LA; Lipson JA; Achacoso N; Rothstein JH; Yaffe MJ; Liang RY; Acton L; McGuire V; Whittemore AS; Rubin DL; Sieh W | May 21, 2016 | PubMed abstract

We report a genome-wide association study of cutaneous squamous cell carcinoma conducted among non-Hispanic white members of the Kaiser Permanente Northern California health care system. The study includes a genome-wide screen of 61,457 members (6,891 cases and 54,566 controls) genotyped on the Affymetrix Axiom European array and a replication phase involving an independent set of 6,410 additional members (810 cases and 5,600 controls). Combined analysis of screening and replication phases identified 10 loci containing single-nucleotide polymorphisms (SNPs) with P-values < 5 × 10(-8). Six loci contain genes in the pigmentation pathway; SNPs at these loci appear to modulate squamous cell carcinoma risk independently of the pigmentation phenotypes. Another locus contains HLA class II genes studied in relation to elevated squamous cell carcinoma risk following immunosuppression. SNPs at the remaining three loci include an intronic SNP in FOXP1 at locus 3p13, an intergenic SNP at 3q28 near TP63, and an intergenic SNP at 9p22 near BNC2. These findings provide insights into the genetic factors accounting for inherited squamous cell carcinoma susceptibility.

Authors: Asgari MM; Wang W; Ioannidis NM; Itnyre J; Hoffmann T; Jorgenson E; Whittemore AS | May 1, 2016 | PubMed abstract

The growing availability of electronic health data provides an opportunity to ascertain diagnosis-specific cases via systematic methods for sample recruitment for clinical research and health services evaluation. We developed and implemented a migraine probability algorithm (MPA) to identify migraine from electronic health records (EHR) in an integrated health plan. We identified all migraine outpatient diagnoses and all migraine-specific prescriptions for a five-year period (April 2008-March 2013) from the Kaiser Permanente, Northern California (KPNC) EHR. We developed and evaluated the MPA in two independent samples, and derived prevalence estimates of medically-ascertained migraine in KPNC by age, sex, and race. The period prevalence of medically-ascertained migraine among KPNC adults during April 2008-March 2013 was 10.3% (women: 15.5%, men: 4.5%). Estimates peaked with age in women but remained flat for men. Prevalence among Asians was half that of whites. We demonstrate the feasibility of an EHR-based algorithm to identify cases of diagnosed migraine and determine that prevalence patterns by our methods yield results comparable to aggregate estimates of treated migraine based on direct interviews in population-based samples. This inexpensive, easily applied EHR-based algorithm provides a new opportunity for monitoring changes in migraine prevalence and identifying potential participants for research studies.

Authors: Pressman A; Jacobson A; Eguilos R; Gelfand A; Huynh C; Hamilton L; Avins A; Bakshi N; Merikangas K | April 1, 2016 | PubMed abstract

Staphylococcus aureus can cause life-threatening infections. Human susceptibility to S. aureus infection may be influenced by host genetic variation. A genome-wide association study (GWAS) in a large health plan-based cohort included biologic specimens from 4701 culture-confirmed S. aureus cases and 45 344 matched controls; 584 535 single-nucleotide polymorphisms (SNPs) were genotyped on an array specific to individuals of European ancestry. Coverage was increased by imputation of >25 million common SNPs, using the 1000 Genomes Reference panel. In addition, human leukocyte antigen (HLA) serotypes were also imputed. Logistic regression analysis, performed under the assumption of an additive genetic model, revealed several imputed SNPs (eg, rs115231074: odds ratio [OR], 1.22 [P = 1.3 × 10(-10)]; rs35079132: OR, 1.24 [P = 3.8 × 10(-8)]) achieving genome-wide significance on chromosome 6 in the HLA class II region. One adjacent genotyped SNP was nearly genome-wide significant (rs4321864: OR, 1.13; P = 8.8 × 10(-8)). These polymorphisms are located near the genes encoding HLA-DRA and HLA-DRB1. Results of further logistic regression analysis, in which the most significant GWAS SNPs were conditioned on HLA-DRB1*04 serotype, showed additional support for the strength of association between HLA class II genetic variants and S. aureus infection. Our study results are the first reported evidence of human genetic susceptibility to S. aureus infection.

Authors: DeLorenze GN; Nelson CL; Scott WK; Allen AS; Ray GT; Tsai AL; Quesenberry CP; Fowler VG | March 1, 2016 | PubMed abstract

Although type 2 diabetes (T2D) predicts glaucoma, the potential for unmeasured confounding has hampered causal conclusions. We performed separate sample genetic instrumental variable analyses using the Genetic Epidemiology Research Study on Adult Health and Aging cohort (n = 69,685; 1995-2013) to estimate effects of T2D on primary open-angle glaucoma (POAG; 3,554 cases). Genetic instrumental variables for overall and mechanism-specific (i.e., linked to T2D via influences on adiposity, ?-cell function, insulin regulation, or other metabolic processes) T2D risk were constructed by using 39 genetic polymorphisms established to predict T2D in other samples. Instrumental variable estimates indicated that T2D increased POAG risk (odds ratio = 2.53, 95% confidence interval: 1.04, 6.11). The instrumental variable for ?-cell dysregulation also significantly predicted POAG (odds ratio?-cell = 5.26, 95% confidence interval: 1.75, 15.85), even among individuals without diagnosed T2D, suggesting that metabolic dysregulation may increase POAG risk prior to T2D diagnosis. The T2D risk variant in the melatonin receptor 1B gene (MTNR1B) predicted risk of POAG independently of T2D status, indicating possible pleiotropic physiological functions of melatonin, but instrumental variable effect estimates were significant even excluding MTNR1B variants. To our knowledge, this is the first genetic instrumental variable study of T2D and glaucoma, providing a novel approach to evaluating this hypothesized relationship. Our findings substantially bolster observational evidence that T2D increases POAG risk.

Authors: Shen L; Walter S; Melles RB; Glymour MM; Jorgenson E | January 15, 2016 | PubMed abstract

Gestational weight gain is known to influence fetal growth. However, it is unclear whether the associations between gestational weight gain and fetal growth vary by trimester. In a diverse cohort of 8,977 women who delivered a singleton between 2011 and 2013, we evaluated the associations between trimester-specific gestational weight gain and infant size for gestational age. Gestational weight gain was categorized per the 2009 Institute of Medicine (IOM) recommendations; meeting the recommendations was the referent. Large for gestational age and small for gestational age were defined as birthweight > 90th percentile or <10th percentile, respectively, based on a national reference standard birthweight distribution. Logistic regression models estimated the odds of having a large or small for gestational age versus an appropriate for gestational age infant. Only gestational weight gain exceeding the IOM recommendations in the 2nd and 3rd trimesters independently increased the odds of delivering a large for gestational age infant (Odds Ratio (95% Confidence Interval): 1st: 1.17 [0.94, 1.44], 2nd: 1.47 [1.13, 1.92], 3rd: 1.70 [1.30, 2.22]). Gestational weight gain below the IOM recommendations increased the likelihood of having a small for gestational age infant in the 2nd trimester only (1.76 [1.23, 2.52]). There was effect modification, and gestational weight gain below the IOM recommendations increased the likelihood of having a small for gestational age infant in the 2nd trimester and only among women with a pre-pregnancy body mass index from 18.5-24.9 kg/m2 (2.06 [1.35, 3.15]). These findings indicate that gestational weight gain during the 2nd and 3rd trimesters is more strongly associated with infant growth. Interventions to achieve appropriate gestational weight gain may optimize infant size at birth.

Authors: Sridhar SB; Xu F; Hedderson MM | January 1, 2016 | PubMed abstract

To evaluate the association between refractive error and the prevalence of glaucoma by race or ethnicity. Cross-sectional study. Kaiser Permanente Northern California Health Plan members with refractive error measured at 35 years of age or older between 2008 and 2014 and with no history of cataract surgery, refractive surgery, or a corneal disorder. We identified 34 040 members with glaucoma or ocular hypertension (OHTN; cases) and 403 398 members without glaucoma (controls). Glaucoma cases were classified as primary angle-closure glaucoma (PACG); 1 of the 4 forms of open-angle glaucoma: primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), pigmentary glaucoma (PIGM), and pseudoexfoliation glaucoma (PEX); or OHTN. Refractive error, expressed as spherical equivalent (SE), was coded as a continuous trait and also as categories. Logistic regression analyses were used to estimate the association between refractive error and the prevalence of glaucoma overall and in specific racial or ethnic groups. The association between refractive error and glaucoma subtypes evaluated as odds ratios (ORs) with 95% confidence intervals (CIs). In controls, the mean SE was -0.59 diopters (D) (standard deviation, 2.62 D). Each 1-D reduction in SE was associated with a 22% decrease in the odds of PACG (OR, 0.78; 95% CI, 0.77-0.80) and with increases in the odds of open-angle glaucoma ranging from 1.23 (95% CI, 1.20-1.26) for PIGM, to 1.07 (95% CI, 1.03-1.11) for PEX, and to 1.05 (95% CI, 1.04-1.06) for OHTN. In addition, we observed a stronger association between myopia and POAG among non-Hispanic whites (OR, 1.12; 95% CI, 1.11-1.13) and NTG among Asians (OR, 1.17; 95% CI, 1.15-1.20) and non-Hispanic whites (OR, 1.19; 95% CI, 1.15-1.22). Myopia was associated with an increased prevalence of all forms of open-angle glaucoma and OHTN, whereas hyperopia was associated with a substantially increased prevalence of PACG. Although high myopia is a strong risk factor for glaucoma subtypes, low and moderate myopia also have a significant effect on glaucoma risk. Additionally, there were moderate racial differences in the association of myopia with the risk of POAG and NTG.

Authors: Shen L; Melles RB; Metlapally R; Barcellos L; Schaefer C; Risch N; Herrinton LJ; Wildsoet C; Jorgenson E | January 1, 2016 | PubMed abstract

The Kaiser Permanente (KP) Research Program on Genes, Environment and Health (RPGEH), in collaboration with the University of California-San Francisco, undertook genome-wide genotyping of >100,000 subjects that constitute the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The project, which generated >70 billion genotypes, represents the first large-scale use of the Affymetrix Axiom Genotyping Solution. Because genotyping took place over a short 14-month period, creating a near-real-time analysis pipeline for experimental assay quality control and final optimized analyses was critical. Because of the multi-ethnic nature of the cohort, four different ethnic-specific arrays were employed to enhance genome-wide coverage. All assays were performed on DNA extracted from saliva samples. To improve sample call rates and significantly increase genotype concordance, we partitioned the cohort into disjoint packages of plates with similar assay contexts. Using strict QC criteria, the overall genotyping success rate was 103,067 of 109,837 samples assayed (93.8%), with a range of 92.1-95.4% for the four different arrays. Similarly, the SNP genotyping success rate ranged from 98.1 to 99.4% across the four arrays, the variation depending mostly on how many SNPs were included as single copy vs. double copy on a particular array. The high quality and large scale of genotype data created on this cohort, in conjunction with comprehensive longitudinal data from the KP electronic health records of participants, will enable a broad range of highly powered genome-wide association studies on a diversity of traits and conditions.

Authors: Kvale MN; Hesselson S; Hoffmann TJ; Cao Y; Chan D; Connell S; Croen LA; Dispensa BP; Eshragh J; Finn A; Gollub J; Iribarren C; Jorgenson E; Kushi LH; Lao R; Lu Y; Ludwig D; Mathauda GK; McGuire WB; Mei G; Miles S; Mittman M; Patil M; Quesenberry CP; Ranatunga D; Rowell S; Sadler M; Sakoda LC; Shapero M; Shen L; Shenoy T; Smethurst D; Somkin CP; Van Den Eeden SK; Walter L; Wan E; Webster T; Whitmer RA; Wong S; Zau C; Zhan Y; Schaefer C; Kwok PY; Risch N | August 1, 2015 | PubMed abstract

Using genome-wide genotypes, we characterized the genetic structure of 103,006 participants in the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging Cohort and analyzed the relationship to self-reported race/ethnicity. Participants endorsed any of 23 race/ethnicity/nationality categories, which were collapsed into seven major race/ethnicity groups. By self-report the cohort is 80.8% white and 19.2% minority; 93.8% endorsed a single race/ethnicity group, while 6.2% endorsed two or more. Principal component (PC) and admixture analyses were generally consistent with prior studies. Approximately 17% of subjects had genetic ancestry from more than one continent, and 12% were genetically admixed, considering only nonadjacent geographical origins. Self-reported whites were spread on a continuum along the first two PCs, indicating extensive mixing among European nationalities. Self-identified East Asian nationalities correlated with genetic clustering, consistent with extensive endogamy. Individuals of mixed East Asian-European genetic ancestry were easily identified; we also observed a modest amount of European genetic ancestry in individuals self-identified as Filipinos. Self-reported African Americans and Latinos showed extensive European and African genetic ancestry, and Native American genetic ancestry for the latter. Among 3741 genetically identified parent-child pairs, 93% were concordant for self-reported race/ethnicity; among 2018 genetically identified full-sib pairs, 96% were concordant; the lower rate for parent-child pairs was largely due to intermarriage. The parent-child pairs revealed a trend toward increasing exogamy over time; the presence in the cohort of individuals endorsing multiple race/ethnicity categories creates interesting challenges and future opportunities for genetic epidemiologic studies.

Authors: Banda Y; Kvale MN; Hoffmann TJ; Hesselson SE; Ranatunga D; Tang H; Sabatti C; Croen LA; Dispensa BP; Henderson M; Iribarren C; Jorgenson E; Kushi LH; Ludwig D; Olberg D; Quesenberry CP; Rowell S; Sadler M; Sakoda LC; Sciortino S; Shen L; Smethurst D; Somkin CP; Van Den Eeden SK; Walter L; Whitmer RA; Kwok PY; Schaefer C; Risch N | August 1, 2015 | PubMed abstract

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis.

Authors: Lapham K; Kvale MN; Lin J; Connell S; Croen LA; Dispensa BP; Fang L; Hesselson S; Hoffmann TJ; Iribarren C; Jorgenson E; Kushi LH; Ludwig D; Matsuguchi T; McGuire WB; Miles S; Quesenberry CP; Rowell S; Sadler M; Sakoda LC; Smethurst D; Somkin CP; Van Den Eeden SK; Walter L; Whitmer RA; Kwok PY; Risch N; Schaefer C; Blackburn EH | August 1, 2015 | PubMed abstract

A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10(-23)) and SLC22A3 (P = 3.2 × 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations.

Authors: Hoffmann TJ; Van Den Eeden SK; Sakoda LC; Jorgenson E; Habel LA; Graff RE; Passarelli MN; Cario CL; Emami NC; Chao CR; Ghai NR; Shan J; Ranatunga DK; Quesenberry CP; Aaronson D; Presti J; Wang Z; Berndt SI; Chanock SJ; McDonnell SK; French AJ; Schaid DJ; Thibodeau SN; Li Q; Freedman ML; Penney KL; Mucci LA; Haiman CA; Henderson BE; Seminara D; Kvale MN; Kwok PY; Schaefer C; Risch N; Witte JS | August 1, 2015 | PubMed abstract

We compared across age-related macular degeneration (AMD) subtypes the effect of AMD risk variants, their predictive power, and heritability. The prevalence of AMD was estimated among active non-Hispanic white Kaiser Permanente Northern California members who were at least 65 years of age as of June 2013. The genetic analysis included 5,170 overall AMD cases ascertained from electronic health records (EHR), including 1,239 choroidal neovascularization (CNV) cases and 1,060 nonexudative AMD cases without CNV, and 23,130 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Imputation was based on the 1000 Genomes Project reference panel. The narrow-sense heritability due to common autosomal single nucleotide polymorphisms (SNPs) was 0.37 for overall AMD, 0.19 for AMD unspecified, 0.20 for nonexudative AMD, and 0.60 for CNV. For the 19 previously reported AMD risk loci, the area under the receiver operating characteristic (ROC) curve was 0.675 for overall AMD, 0.640 for AMD unspecified, 0.678 for nonexudative AMD, and 0.766 for CNV. The individual effects on the risk of AMD for 18 of the 19 SNPs were in a consistent direction with those previously reported, including a protective effect of the APOE ?4 allele. Conversely, the risk of AMD was significantly increased in carriers of the ?2 allele. These findings provide an independent confirmation of many of the previously identified AMD risk loci, and support a potentially greater role of genetic factors in the development of CNV. The replication of established associations validates the use of EHR in genetic studies of ophthalmologic traits.

Authors: Shen L; Hoffmann TJ; Melles RB; Sakoda LC; Kvale MN; Banda Y; Schaefer C; Risch N; Jorgenson E | July 1, 2015 | PubMed abstract

The first-line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome-wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2,027 subjects in Kaiser Permanente’s Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol-related SUA reduction, first in the largest ethnic group, non-Hispanic white (NHW) subjects, and then in a stratified transethnic meta-analysis. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (P = 2 × 10(-8) ), and a missense allele (rs2231142) was associated with a reduced response (P = 3 × 10(-7) ) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug.

Authors: Wen CC; Yee SW; Liang X; Hoffmann TJ; Kvale MN; Banda Y; Jorgenson E; Schaefer C; Risch N; Giacomini KM | May 1, 2015 | PubMed abstract

An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of this approach hinges on the accuracy of rare variant imputation, which remains controversial. For example, a recent study suggested that one cannot adequately impute the HOXB13 G84E mutation associated with prostate cancer risk (carrier frequency of 0.0034 in European ancestry participants in the 1000 Genomes Project). We show here that-by utilizing the 1000 Genomes Project data plus an enriched reference panel of mutation carriers-we were able to accurately impute the G84E mutation into a large cohort of 83,285 non-Hispanic White participants from the Kaiser Permanente Research Program on Genes, Environment and Health Genetic Epidemiology Research on Adult Health and Aging cohort. Imputation authenticity was confirmed via a novel classification and regression tree method, and then empirically validated analyzing a subset of these subjects plus an additional 1,789 men from the California Men’s Health Study specifically genotyped for the G84E mutation (r2 = 0.57, 95% CI = 0.37-0.77). We then show the value of this approach by using the imputed data to investigate the impact of the G84E mutation on age-specific prostate cancer risk and on risk of fourteen other cancers in the cohort. The age-specific risk of prostate cancer among G84E mutation carriers was higher than among non-carriers, and this difference increased with age. Risk estimates from Kaplan-Meier curves were 36.7% versus 13.6% by age 72, and 64.2% versus 24.2% by age 80, for G84E mutation carriers and non-carriers, respectively (p = 3.4×10-12). The G84E mutation was also suggestively associated with an increase in risk for the following cancer sites by approximately 50% in a pleiotropic manner: breast, non-Hodgkin’s lymphoma, kidney, bladder, melanoma, endometrium, and pancreas (p = 0.042).

Authors: Hoffmann TJ; Sakoda LC; Shen L; Jorgenson E; Habel LA; Liu J; Kvale MN; Asgari MM; Banda Y; Corley D; Kushi LH; Quesenberry CP; Schaefer C; Van Den Eeden SK; Risch N; Witte JS | January 1, 2015 | PubMed abstract

Inguinal hernia repair is one of the most commonly performed operations in the world, yet little is known about the genetic mechanisms that predispose individuals to develop inguinal hernias. We perform a genome-wide association analysis of surgically confirmed inguinal hernias in 72,805 subjects (5,295 cases and 67,510 controls) and confirm top associations in an independent cohort of 92,444 subjects with self-reported hernia repair surgeries (9,701 cases and 82,743 controls). We identify four novel inguinal hernia susceptibility loci in the regions of EFEMP1, WT1, EBF2 and ADAMTS6. Moreover, we observe expression of all four genes in mouse connective tissue and network analyses show an important role for two of these genes (EFEMP1 and WT1) in connective tissue maintenance/homoeostasis. Our findings provide insight into the aetiology of hernia development and highlight genetic pathways for studies of hernia development and its treatment.

Authors: Jorgenson E; Makki N; Shen L; Chen DC; Tian C; Eckalbar WL; Hinds D; Ahituv N; Avins A | January 1, 2015 | PubMed abstract

Exome and whole-genome sequencing studies are becoming increasingly common, but little is known about the accuracy of the genotype calls made by the commonly used platforms. Here we use replicate high-coverage sequencing of blood and saliva DNA samples from four European-American individuals to estimate lower bounds on the error rates of Complete Genomics and Illumina HiSeq whole-genome and whole-exome sequencing. Error rates for nonreference genotype calls range from 0.1% to 0.6%, depending on the platform and the depth of coverage. Additionally, we found (1) no difference in the error profiles or rates between blood and saliva samples; (2) Complete Genomics sequences had substantially higher error rates than Illumina sequences had; (3) error rates were higher (up to 6%) for rare or unique variants; (4) error rates generally declined with genotype quality (GQ) score, but in a nonlinear fashion for the Illumina data, likely due to loss of specificity of GQ scores greater than 60; and (5) error rates increased with increasing depth of coverage for the Illumina data. These findings, especially (3)-(5), suggest that caution should be taken in interpreting the results of next-generation sequencing-based association studies, and even more so in clinical application of this technology in the absence of validation by other more robust sequencing or genotyping methods.

Authors: Wall JD; Tang LF; Zerbe B; Kvale MN; Kwok PY; Schaefer C; Risch N | November 1, 2014 | PubMed abstract

The objective of the study was to evaluate the association between gestational weight gain, per the 2009 Institute of Medicine (IOM) recommendations, and offspring overweight/obesity at 2-5 years of age. This was a prospective cohort study of 4145 women who completed a health survey (2007-2009) and subsequently delivered a singleton at Kaiser Permanente Northern California (2007-2010). Childhood overweight/obesity was defined as a body mass index (BMI) z-score of the 85th percentile or greater of the Centers for Disease Control and Prevention child growth standards. Gestational weight gain was categorized according to the 2009 IOM recommendations. Logistic regression was used; meeting the IOM recommendations was the referent. Exceeding the IOM recommendations was associated with a 46% increase in odds of having an overweight/obese child (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.17-1.83), after adjusting for maternal prepregnancy BMI, race/ethnicity, age at delivery, education, child age, birthweight, gestational age at delivery, gestational diabetes, parity, infant sex, total metabolic equivalents, and dietary pattern. The OR (95% CI) for childhood overweight/obesity among women gaining below the IOM recommendations was 1.23 (0.88-1.71). The associations between gaining outside the IOM recommendations and childhood obesity were stronger among women with a normal prepregnancy BMI (OR, 1.63; 95% CI, 1.03-2.57) (below); OR, 1.79; 95% CI, 1.32-2.43) (exceeded). Gestational weight gain outside the IOM recommendations is associated with increased odds of childhood overweight/obesity, independent of several potential confounders and mediators. Gestational weight gain had a greater impact on childhood overweight/obesity among normal-weight women, suggesting that the effect may be independent of genetic predictors of obesity.

Authors: Sridhar SB; Darbinian J; Ehrlich SF; Markman MA; Gunderson EP; Ferrara A; Hedderson MM | September 1, 2014 | PubMed abstract

BACKGROUND: Studies of the impact of type 2 diabetes on the prevalence and incidence of lower urinary tract symptoms (LUTS) among men have provided divergent results. We sought to examine this issue using two large and diverse cohorts. METHODS: This study used questionnaire and clinical data from two large multiethnic cohorts, the California Men’s Health Study (CMHS) and Research Program in Genes, Environment and Health (RPGEH). Diabetes characteristics data were derived from questionnaire and Diabetes Registry data. LUTS were measured using a standardized scale. Socioeconomic and comorbidity data were obtained by self-report. Multivariable logistic regression analysis was used to examine the association between baseline DM status and prevalence and incidence of LUTS, with adjustment for potential confounding variables. RESULTS: We found type 2 diabetes to be associated with prevalent LUTS (odds ratio (OR) = 1.32, 95% confidence interval (CI) 1.26, 1.38). The association was stronger among men with type 2 diabetes who were on active pharmaceutical treatment and had it for a longer duration. No association was observed between type 2 diabetes and new onset LUTS. CONCLUSIONS: Type 2 diabetes increases the risk of LUTS.

Authors: Van Den Eeden SK; Ferrara A; Shan J; Jacobsen SJ; Quinn VP; Haque R; Quesenberry CP | January 1, 2013 | PubMed abstract

PURPOSE: We examined whether there are racial/ethnic disparities in lower urinary tract symptoms in men. MATERIALS AND METHODS: Racial/ethnic disparities were examined using the American Urological Association symptom index in 2 large cohorts, including the California Men’s Health Study and the Research Program in Genes, Environment and Health. Prevalence and incidence were calculated in each age and race/ethnicity strata. Multivariate analysis was done to assess the association between race/ethnicity and lower urinary tract symptoms. RESULTS: The lower urinary tract symptom prevalence increased with age in each racial/ethnic category (p <0.05). The mean +/- SD age adjusted American Urological Association symptom index score for black, Hispanic, other/mixed, nonHispanic white and Asian men was 9.57 +/- 5.83, 9.35 +/- 6.30, 9.32 +/- 6.22, 8.99 +/- 5.89 and 8.41 +/- 5.59, respectively. In multivariate models Hispanic and black men were at increased risk for moderate lower urinary tract symptoms than white men while only Hispanic men were at higher risk for severe lower urinary tract symptoms. Asian men were at lower risk for moderate or severe lower urinary tract symptoms than white men. The incident rate of lower urinary tract symptoms increased with increasing baseline age for almost all racial/ethnic groups (range 32% to 56%). Asian and Hispanic men were at lower risk for incident lower urinary tract symptoms than white men even after adjusting for sociodemographic factors, health related behaviors and comorbidity. CONCLUSIONS: Racial/ethnic disparities in lower urinary tract symptoms persist after accounting for putative and established risk factors.

Authors: Van Den Eeden SK; Shan J; Jacobsen SJ; Aaronsen D; Haque R; Quinn VP; Quesenberry CP Jr; Urologic Diseases in America Project | January 1, 2012 | PubMed abstract

Four custom Axiom genotyping arrays were designed for a genome-wide association (GWA) study of 100,000 participants from the Kaiser Permanente Research Program on Genes, Environment and Health. The array optimized for individuals of European race/ethnicity was previously described. Here we detail the development of three additional microarrays optimized for individuals of East Asian, African American, and Latino race/ethnicity. For these arrays, we decreased redundancy of high-performing SNPs to increase SNP capacity. The East Asian array (712,930 SNPs) was designed using greedy pairwise SNP selection. However, removing SNPs from the target set based on imputation coverage is more efficient than pairwise tagging. Therefore, we developed a novel hybrid SNP selection method for the African American and Latino arrays utilizing rounds of greedy pairwise SNP selection, followed by removal from the target set of SNPs covered by imputation. The arrays provide excellent genome-wide coverage and are valuable additions for large-scale GWA studies.

Authors: Hoffmann TJ; Zhan Y; Kvale MN; Hesselson SE; Gollub J; Iribarren C; Lu Y; Mei G; Purdy MM; Quesenberry C; Rowell S; Shapero MH; Smethurst D; Somkin CP; Van den Eeden SK; Walter L; Webster T; Whitmer RA; Finn A; Schaefer C; Kwok PY; Risch N | December 1, 2011 | PubMed abstract

BACKGROUND: Proper understanding of the roles of, and interactions between genetic, lifestyle, environmental and psycho-social factors in determining the risk of development and/or progression of chronic diseases requires access to very large high-quality databases. Because of the financial, technical and time burdens related to developing and maintaining very large studies, the scientific community is increasingly synthesizing data from multiple studies to construct large databases. However, the data items collected by individual studies must be inferentially equivalent to be meaningfully synthesized. The DataSchema and Harmonization Platform for Epidemiological Research (DataSHaPER; http://www.datashaper.org) was developed to enable the rigorous assessment of the inferential equivalence, i.e. the potential for harmonization, of selected information from individual studies. METHODS: This article examines the value of using the DataSHaPER for retrospective harmonization of established studies. Using the DataSHaPER approach, the potential to generate 148 harmonized variables from the questionnaires and physical measures collected in 53 large population-based studies (6.9 million participants) was assessed. Variable and study characteristics that might influence the potential for data synthesis were also explored. RESULTS: Out of all assessment items evaluated (148 variables for each of the 53 studies), 38% could be harmonized. Certain characteristics of variables (i.e. relative importance, individual targeted, reference period) and of studies (i.e. observational units, data collection start date and mode of questionnaire administration) were associated with the potential for harmonization. For example, for variables deemed to be essential, 62% of assessment items paired could be harmonized. CONCLUSION: The current article shows that the DataSHaPER provides an effective and flexible approach for the retrospective harmonization of information across studies. To implement data synthesis, some additional scientific, ethico-legal and technical considerations must be addressed. The success of the DataSHaPER as a harmonization approach will depend on its continuing development and on the rigour and extent of its use. The DataSHaPER has the potential to take us closer to a truly collaborative epidemiology and offers the promise of enhanced research potential generated through synthesized databases.

Authors: Fortier, Isabel; Doiron, Dany; Little, Julian; Ferretti, Vincent; L'Heureux, François; Stolk, Ronald P.; Knoppers, Bartha M.; Hudson, Thomas J.; Burton, Paul R.; International Harmonization Initiative | October 1, 2011 | PubMed abstract

The success of genome-wide association studies has paralleled the development of efficient genotyping technologies. We describe the development of a next-generation microarray based on the new highly-efficient Affymetrix Axiom genotyping technology that we are using to genotype individuals of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH). The array contains 674,517 SNPs, and provides excellent genome-wide as well as gene-based and candidate-SNP coverage. Coverage was calculated using an approach based on imputation and cross validation. Preliminary results for the first 80,301 saliva-derived DNA samples from the RPGEH demonstrate very high quality genotypes, with sample success rates above 94% and over 98% of successful samples having SNP call rates exceeding 98%. At steady state, we have produced 462 million genotypes per week for each Axiom system. The new array provides a valuable addition to the repertoire of tools for large scale genome-wide association studies.

Authors: Hoffmann TJ; Kvale MN; Hesselson SE; Zhan Y; Aquino C; Cao Y; Cawley S; Chung E; Connell S; Eshragh J; Ewing M; Gollub J; Henderson M; Hubbell E; Iribarren C; Kaufman J; Lao RZ; Lu Y; Ludwig D; Mathauda GK; McGuire W; Mei G; Miles S; Purdy MM; Quesenberry C; Ranatunga D; Rowell S; Sadler M; Shapero MH; Shen L; Shenoy TR; Smethurst D; Van den Eeden SK; Walter L; Wan E; Wearley R; Webster T; Wen CC; Weng L; Whitmer RA; Williams A; Wong SC; Zau C; Finn A; Schaefer C; Kwok PY; Risch N | August 1, 2011 | PubMed abstract