Participants Of European Ancestry Research Articles

Transcriptome-wide association study in UK Biobank Europeans identifies associations with blood cell traits.

Previous genome-wide association studies (GWAS) of hematological traits have identified over 10 000 distinct trait-specific risk loci. However, at these loci, the underlying causal mechanisms remain incompletely characterized. To elucidate novel biology and better understand causal mechanisms at known loci, we performed a transcriptome-wide association study (TWAS) of 29 hematological traits in 399 835 UK Biobank (UKB) participants of European ancestry using gene expression prediction models trained from whole blood RNA-seq data in 922 individuals. We discovered 557 gene-trait associations for hematological traits distinct from previously reported GWAS variants in European populations. Among the 557 associations, 301 were available for replication in a cohort of 141 286 participants of European ancestry from the Million Veteran Program. Of these 301 associations, 108 replicated at a strict Bonferroni adjusted threshold ($\alpha$= 0.05/301). Using our TWAS results, we systematically assigned 4261 out of 16 900 previously identified hematological trait GWAS variants to putative target genes. Compared to coloc, our TWAS results show reduced specificity and increased sensitivity in external datasets to assign variants to target genes.

Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.

Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.

A Mendelian randomization study on the effect of 25-hydroxyvitamin D levels on periodontitis.

Twenty five-hydroxy vitamin D (25OHD) levels have been proposed to protect against periodontitis based on in vitro and observational studies but evidence from long-term randomized controlled trials (RCTs) is lacking. This study tested whether genetically proxied 25OHD is associated with periodontitis using Mendelian randomization (MR). Genetic variants strongly associated with 25OHD in a genome-wide association study (GWAS) of 417,580 participants of European ancestry were used as instrumental variables, and linked to GWAS summary data of 17,353 periodontitis cases and 28,210 controls. In addition to the main analysis using an inverse variance weighted (IVW) model, we applied additional robust methods to control for pleiotropy. We also undertook sensitivity analyses excluding single nucleotide polymorphisms (SNPs) used as instruments with potential pleiotropic effects and used a second 25OHD GWAS for replication. We identified 288 SNPs to be genome-wide significant for 25OHD, explaining 7.0% of the variance of 25OHD levels and providing ≥90% power to detect an odds ratio (OR) of ≤ 0.97. MR analysis suggested that a 1 standard deviation increase in natural log-transformed 25OHD was not associated with periodontitis risk (IVW OR = 1.04; 95% confidence interval (CI): 0.97-1.12; P-value = 0.297). The robust models, replication, and sensitivity analyses were coherent with the primary analysis. Collectively, our findings suggest that 25OHD levels are unlikely to have a substantial effect on the risk of periodontitis, but large long-term RCTs are needed to derive definitive evidence on the causal role of 25OHD in periodontitis.

Non-Causal Effects of Asthma on COVID-19 Susceptibility and Severity.

Background: Asthma is observationally associated with an increased risk of COVID-19, but the causality remains unclear. We aim to determine whether there is a casual role of asthma in susceptibility to SARS-CoV-2 infection or COVID-19 severity. Methods: Instrumental variables (IVs) for asthma and moderate-to-severe asthma were obtained from publicly available summary statistics from the most recent and largest genome-wide association study (GWAS), including 394 283 and 57 695 participants of European ancestry, respectively. The corresponding data for COVID-19 susceptibility, hospitalization and severe-disease were derived from the COVID-19 Host Genetics Initiative GWAS meta-analysis of up to 1 683 768 individuals of European descent. Causality was inferred between correlated traits by Mendelian Randomization analyses. Inverse-variance weighted method was used as the primary MR estimates and multiple alternate approaches and several sensitivity analyses were also conducted. Results: Our MR analysis revealed no causal effects of asthma on COVID-19 susceptibility, hospitalization or severe disease, with odds ratio (OR) of 0.994 (95% CI: 0.962–1.027), 1.020 (95% CI: 0.955–1.089), and 0.929 (95% CI: 0.836–1.032), respectively. Furthermore, using genetic variants for moderate-to-severe asthma, a similar pattern of results was observed for COVID-19 susceptibility (OR: 0.988, 95% CI: 0.946–1.031), hospitalization (OR: 0.967, 95% CI: 0.906–1.031), and severe disease (OR: 0.911, 95% CI: 0.823–1.009). The association of asthma and moderate-to-severe asthma with COVID-19 was overall robust to sensitivity analyses. Conclusion: Genetically predicted asthma was not associated with susceptibility to, or severity of, COVID-19 disease, indicating that asthma is unlikely to be a causal factor in the development of COVID-19.

Maternal Hypertension Increases Risk of Preeclampsia and Low Fetal Birthweight: Genetic Evidence From a Mendelian Randomization Study.

Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing preeclampsia or eclampsia, and low fetal birthweight. Uncorrelated single-nucleotide polymorphisms associated systolic blood pressure (SBP), body mass index, type 2 diabetes, LDL (low-density lipoprotein) with cholesterol, smoking, urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate at genome-wide significance in studies of 298 957 to 1 201 909 European ancestry participants were selected as instrumental variables. A 2-sample Mendelian randomization study was performed with primary outcome of preeclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight. Higher genetically predicted SBP was associated increased risk of PET (odds ratio [OR] per 1-SD SBP increase 1.90 [95% CI=1.45-2.49]; P=3.23×10-6) and reduced birthweight (OR=0.83 [95% CI=0.79-0.86]; P=3.96×10-18), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase =1.67 [95% CI=1.44-1.94]; P=7.45×10-12; and OR per logOR increase type 2 diabetes =1.11 [95% CI=1.04-1.19]; P=1.19×10-3), but not with reduced birthweight. Our results provide evidence for causal effects of SBP, body mass index, and type 2 diabetes on PET and identify that SBP is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.

Abstract PO-164: Pathogenic variants in breast cancer risk genes in Latinas

Abstract Introduction: Pathogenic variants (PVs) in high- and intermediate-penetrance breast cancer susceptibility genes have large effects on disease risk. While individual PVs are rare, in aggregate, they markedly contribute to breast cancer risk in women of European ancestry in the general population. We examined the association with risk of developing breast cancer in Latinas. Methods: We conducted a pooled case-control analysis of breast cancer in Latinas from the San Francisco Bay Area, Los Angeles, and Mexico (4,172 cases and 3,692 controls). Case ascertainment included 2,095 participants from high-risk breast cancer studies (age below 50 years at breast cancer diagnosis, family history, or bilateral breast cancer) and 5,769 from general population studies. We determined presence of a rare PV in nine known breast cancer risk genes (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, PTEN, RAD51C, and TP53). We examined associations between PVs in each gene and breast cancer using multivariable logistic regression models, adjusted for age and ancestry. Secondary analyses were stratified by age, family history, or Indigenous American (IA) ancestry. Results: PVs in known risk genes were detected in 7.0% of cases and 1.7% of controls in participants from general population studies. Odds ratios (OR) for breast cancer in those with PVs in BRCA1, BRCA2, CHEK2, PALB2, and TP53 were 15.7 (95% CI: 5.7-64.8), 7.0 (95% CI: 3.7-14.4), 1.9 (95% CI: 1.0-4.0), 6.1 (95% CI: 3.1-13.9), and 3.7 (95% CI: 1.1-16.2) respectively. PVs in ATM (OR: 1.2, 95% CI: 0.7-2.1), BARD1 (OR: 1.5, 95% CI: 0.3-10.4), PTEN (PVs in 4 cases and 0 controls), and RAD51C (OR: 1.5, 95% CI: 0.2-11.5) were not significantly associated with breast cancer. Among cases, those with age&amp;lt;50 at diagnosis or with family history of breast cancer had increased odds of having a PV, with ORs of 1.4 (95% CI: 1.0-1.9) and 2.3 (95% CI: 1.4-4.0), respectively. IA above the median was associated with increased odds of having a PV among cases (OR: 1.8; 95% CI: 1.4-2.5) but not among controls. Discussion: Among Latina participants, having a PV in any of the nine genes was associated with increased risk of breast cancer. As expected, cases who were younger or had a family history of breast cancer were more likely to have a PV. In addition, cases but not controls with high IA were more likely to have a PV. The higher prevalence of PVs among high IA cases but not controls may be due to the younger age of these women and/or lower prevalence of other environmental risk factors. Our PV prevalence estimates among Latinas were similar to those previously found among European ancestry participants. Our results suggest that there may be clinical utility in testing for rare PVs in breast cancer risk genes among those in the general population. Citation Format: Jovia L Nierenberg, Aaron Adamson, Yuan C. Ding, Yiwey Shieh, Donglei Hu, Scott Huntsman, Esther M. John, Gabriela Torres-Mejia, Christopher A. Haiman, Lawrence H. Kushi, Charite N. Ricker, Linda Steele, Robin Lee, Jeffrey N. Weitzel, Laura Fejerman, Elad Ziv, Susan L. Neuhausen. Pathogenic variants in breast cancer risk genes in Latinas [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-164.

APOL1 G3 Variant Is Associated with Cardiovascular Mortality and Sudden Cardiac Death in Patients Receiving Maintenance Hemodialysis of European Ancestry

Introduction: The G1 and G2 variants in the APOL1 gene convey high risk for the progression of chronic kidney disease in African Americans. The G3 variant in APOL1 is more common in patients of European ancestry (EA); outcomes associated with this variant have not been explored previously in EA patients receiving dialysis. Methods: DNA was collected from approximately half of the patients enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial and genotyped for the G3 variants. We utilized an additive genetic model to test associations of G3 with the EVOLVE adjudicated endpoints of all-cause mortality, cardiovascular mortality, sudden cardiac death (SCD), and heart failure. EA and African ancestry samples were analyzed separately. Validation was done in the Vanderbilt BioVU using ICD codes for cardiovascular events that parallel the adjudicated endpoints in EVOLVE. Results: In EVOLVE, G3 in EA patients was associated with the adjudicated endpoints of cardiovascular mortality and SCD. In a validation cohort from the Vanderbilt BioVU, cardiovascular events and cardiovascular mortality defined by ICD codes showed similar associations in EA participants who had been on dialysis for 2 to <5 years. Discussion/Conclusions: G3 in APOL1 variant was associated with cardiovascular events and cardiovascular mortality in the EA patients receiving dialysis. This suggests that variations in the APOL1 gene that differ in populations of different ancestry may contribute to cardiovascular disease.

Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies

BackgroundDNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer.MethodsUsing data from four prospective case–control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage.ResultsNone of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath ‘age acceleration’ (AA): OR per SD = 1.02, 95%CI: 0.95–1.10; AA-Hannum: OR = 1.03, 95%CI:0.95–1.12; PhenoAge: OR = 1.01, 95%CI: 0.94–1.09 and GrimAge: OR = 1.03, 95%CI: 0.94–1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01–1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics.ConclusionWe found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.

Inclusion of Smoking Data in Cardiovascular Disease Risk Estimation

Former heavy smokers (ie, those with ≥20 pack-years of smoking) may have higher atherosclerotic cardiovascular disease (ASCVD) risk than never smokers for up to 16 years after smoking cessation. However, the 2013 pooled cohort equations (PCE) do not account for pack-years of smoking and only consider current vs noncurrent smoking status without distinguishing former smokers from never smokers. To assess the predictive utility of smoking history when added to the PCE using data from 18 400 person examinations among Framingham offspring participants. This is a retrospective analysis of prospectively collected data from the Framingham Heart Study, a community-based cohort. Framingham Heart Study offspring cohort participants attending their first examination (1971-1975) who were followed-up through December 2016 were included. Self-reported current/former/never smoking status, pack-years smoked, and years since quitting. Incident ASCVD (myocardial infarction, fatal/nonfatal ischemic stroke, coronary heart disease death). Of 3908 patients, there were 358 and 197 events among 1895 men and 2013 women, respectively, with a mean (SD) age of 55 (9.5) years. Ever smoking prevalence was high (6474 men [77%] and 7760 women [78%]), as were median pack-years (men: 39; women: 32 overall person examinations). Four sex-specific ASCVD risk prediction models were built using pooled-repeated Cox proportional hazards regression. The PCEs were was fit in this sample with continuous predictors on their natural scale (ie, not logarithmically transformed) as well as polynomials accounting for nonlinearity and then cumulatively adjusted for former smoking, pack-years, and years since quitting. Models were compared via change in C statistic, continuous net reclassification improvement (NRI[>0]), and relative integrated discrimination improvement (rIDI). Including former smoking status, pack-years, and years since quitting had significant but modest NRI(>0) and rIDI values compared with the PCE with continuous variables on their natural scale in both sexes (men: NRI[>0] = 0.23; rIDI = 0.19; women: NRI[>0] = 0.34, rIDI = 0.11; change in C statistic = 0.01 for both). Former smoking, pack-years, and years since quitting significantly improved ASCVD risk prediction in this sample. The Framingham Heart Study offspring cohort is largely composed of non-Hispanic White participants of European ancestry. If results are validated in cohorts of race and ethnicity groups other than White, these variables could be considered for inclusion in future ASCVD risk prediction models.

Polygenic architecture and cardiovascular risk of familial combined hyperlipidemia

Background and aimsFamilial combined hyperlipidemia (FCHL) is one of the most common inherited lipid phenotypes, characterized by elevated plasma concentrations of apolipoprotein B-100 and triglycerides. The genetic inheritance of FCHL remains poorly understood. The goals of this study were to investigate the polygenetic architecture and cardiovascular risk associated with FCHL. Methods and resultsWe identified individuals with an FCHL phenotype among 349,222 unrelated participants of European ancestry in the UK Biobank using modified versions of 5 different diagnostic criteria. The prevalence of the FCHL phenotype was 11.44% (n = 39,961), 5.01% (n = 17,485), 1.48% (n = 5,153), 1.10% (n = 3,838), and 0.48% (n = 1,688) according to modified versions of the Consensus Conference, Dutch, Mexico, Brunzell, and Goldstein criteria, respectively. We performed discovery, case-control genome-wide association studies for these different FCHL criteria and identified 175 independent loci associated with FCHL at genome-wide significance. We investigated the association of genetic and clinical risk with FCHL and found that polygenic susceptibility to hypercholesterolemia or hypertriglyceridemia and features of metabolic syndrome were associated with greater prevalence of FCHL. Participants with an FCHL phenotype had a similar risk of incident coronary artery disease compared to participants with monogenic familial hypercholesterolemia (adjusted hazard ratio vs controls [95% confidence interval]: 2.72 [2.31–3.21] and 1.90 [1.30–2.78]). ConclusionsThese results suggest that, rather than being a single genetic entity, the FCHL phenotype represents a polygenic susceptibility to dyslipidemia in combination with metabolic abnormalities. The cardiovascular risk associated with an FCHL phenotype is similar to that of monogenic familial hypercholesterolemia, despite being ∼5x more common.

Common and rare variants in topologically associated domains for cognitive function in South Asians from the LASI-DAD Study.

Genome-wide association studies (GWAS) in European ancestry (EA) participants have identified many loci associated with cognitive function. However, the association between variants at these loci and cognition has not been evaluated in South Asians. Due to ancestral genetic heterogeneity, the functional SNPs/variants in South Asians may be different than those identified in EA GWAS, even if the same genes/genomic regions are associated. Topologically associated domains (TADs), a basic unit of chromosome foldin, reflect a high level of intradomain interaction. This study used a region-based approach to investigate whether the TAD regions tagged by SNPs identified in EA GWAS were associated with a general cognitive factor and the Hindi version of the Mini-Mental State Examination (HMSE) score in 932 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD). Participants were genotyped using the Illumina Global Screening Array and imputed to 1000G Phase 3v5. The sequence kernel association test (SKAT and SKAT-O) was used to assess the joint effects of multiple SNPs/variants in 146 TAD regions after controlling for age, gender, and population structure, with or without education. We used two weighting schemes: equal weight for all SNPs/variants (beta(1,1)), and upweighting of rare variants (beta(1,25)). Due to the large size of each TAD region, we used a moving window approach (window size: 300 variants). Three windows (in TAD region tagged by rs6819372) were significantly associated with the general cognitive factor using the equal SNP/variant weighting approach (FDR<0.1). Using the rare variant weighting approach, five windows (in TAD regions tagged by rs889956, rs7494275, and rs830386) were significantly associated with the general cognitive factor after adjusting for education. Those windows, however, often do not overlap with the SNPs identified from EA GWAS. Given that the associated regions often do not contain the EA GWAS SNPs GWAS, there may be substantial genetic heterogeneity between EA and South Asians even when the same gene regions are associated with cognition. Future work is needed to identify the specific variants that influence cognitive function in South Asians.

Genetically Determined Inflammatory Biomarkers and the Risk of Heart Failure: A Mendelian Randomization Study.

Background: Positive associations between inflammatory biomarkers and the risk of heart failure (HF) have been reported in conventional observational studies. However, the causal effects of inflammatory biomarkers on HF have not been fully elucidated. We conducted a Mendelian randomization (MR) study to examine the possible etiological roles of inflammatory biomarkers in HF.Methods: Summary statistical data for the associations between single nucleotide polymorphisms (SNPs) and C-reactive protein (CRP), fibrinogen, and components of the interleukin-1 (IL-1)-interleukin-6 (IL-6) inflammatory signaling pathway, namely, interleukin-1β (IL-1β), IL-1 receptor antagonist (IL-1ra), IL-6, and soluble IL-6 receptor (sIL-6r), were obtained from genome-wide association studies (GWASs) for individuals of European descent. The GWAS dataset of 977,323 participants of European ancestry, which included 47,309 HF cases and 930,014 controls, was collected to identify genetic variants underlying HF. A two-sample Mendelian randomization framework was implemented to examine the causality of the association between these inflammatory biomarkers and HF.Results: Our MR analyses found that genetically determined CRP and fibrinogen were not causally associated with HF risk (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.84–1.02, p = 0.15; OR = 0.94, 95% CI = 0.55–1.58, p = 0.80, respectively). These findings remained consistent using different Mendelian randomization methods and in sensitivity analyses. For the IL-1-IL-6 pathway, causal estimates for IL-6 (OR = 0.86, 95% CI 0.81–0.91, p < 0.001), but not for IL-1β, IL-1ra, or sIL-6r, were significant. However, the association between genetically determined IL-6 and HF risk became non-significant after excluding SNPs with potential pleiotropy (OR = 0.89, 95% CI = 0.77–1.03, p = 0.12).Conclusion: Our study did not identify convincing evidence to support that CRP and fibrinogen, together with their upstream IL-1-IL-6 signaling pathway, were causally associated with HF risk.

Abstract 14154: Genome-Wide Association Study of Dilated Cardiomyopathy in the VA Million Veteran Program

Introduction: Rare, Mendelian drivers of dilated cardiomyopathy (DCM) are well-established, but the contribution of common genetic variation to DCM risk has emerged more recently. As common variant discovery has largely relied on genome wide association studies (GWAS) of prospectively recruited DCM cases, we sought to conduct a GWAS of retrospectively-defined DCM from a large biobank. Methods: We used electronic health record-based phenotyping to define DCM in the VA Million Veteran Program (MVP), performed ancestry-specific GWAS in MVP participants of European and African genetic ancestry, and then conducted a trans-ethnic meta-analysis. We pursued replication of sentinel DCM single nucleotide polymorphisms (SNPs) in the UK Biobank. We further assessed the association of sentinel DCM SNPs with subclinical cardiac magnetic resonance imaging measures of left ventricular (LV) structure and function in UK Biobank, and with hypertrophic cardiomyopathy (HCM) in MVP. Results: Among 459,937 MVP study participants, mean age was 61.5, 43,971 (9.6%) were female, and 5,597 had DCM (N=3,786 European ancestry, N=1,811 African ancestry). In trans-ethnic meta-analysis, we identified eight genomic regions associated with DCM at genome-wide significance (P &lt; 5x10 -8 ). These included three of four known DCM associations near HSPB7 , LSM3 , and BAG3 ; and five novel genomic regions near SLC39A8 , CDKN1A , CD36 , NEDD4L , and MAP3K7CL . Three of the novel regions (at CDKN1A , NEDD4L , and MAP3K7CL ) were replicated in UK Biobank (all p&lt;8.0E-4; N=899 DCM cases, 449,574 controls). SNPs associated with increased DCM risk also associated with increased LV end-diastolic and end-systolic volumes and lower LV ejection fraction in UK Biobank participants without clinical heart failure or cardiomyopathy (N &gt; 31,614; all p &lt; 0.01). Sentinel SNPs for DCM also showed a trend towards an opposite direction of association with HCM in MVP (N=1,533 HCM cases, 465,877 controls). Conclusions: We conducted the largest GWAS of DCM to date, and identified five novel, common genetic loci associated with DCM with replication of three novel loci in an external cohort. Our findings highlight the potential to leverage emerging biobank populations to scale common variant discovery for DCM.

Abstract 10714: The Role of Interleukin-6 in Heart Failure and Its Subtypes: Results from Mendelian Randomization and Mediation Analysis

Introduction: Heart failure (HF) increases morbidity, mortality, and costs, with complex pathogenic mechanisms. Interleukin-6 (IL-6) is a key cytokine and immune regulator with broad impact on inflammation – a critical component of HF pathophysiology. Circulating levels of IL-6 receptor (IL-6R) determines the activity of the IL-6 signaling pathway. We aim to estimate the causal effect of the IL-6R on HF and two clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF) in a Mendelian Randomization (MR) framework including mediators. Hypothesis: Plausible causal associations between IL-6R and HF, HFrEF and HFpEF are mediated by body mass index (BMI) or coronary artery disease (CAD). Methods: Two-sample MR analyses were conducted using genetic association results for composite HF, HFrEF and HFpEF among &gt;300,000 MVP participants of European ancestry. Thirty-four independent genetic variants within 250 kb from the IL6R gene associated with plasma IL-6R levels were used as genetic instrumental variables. We estimated the direct effect of IL-6R levels on HF and subtypes, and the indirect effect mediated through BMI and CAD. Results: Causal effects of IL-6R on composite HF, HFrEF and HFpEF were estimated as odds ratios (OR): 0.97 (CI 0.96-0.99, p=0.02), 0.96 (CI 0.93-0.98, p=0.003) and 1.00 (CI 0.97-1.03, p=0.89), respectively. Mediation analyses for composite HF and HFrEF showed significant mediation effects by CAD, with ORs 0.98 (CI 0.97-0.99) and 0.98 (CI 0.96-1.00), respectively. No mediation effect of BMI was identified. Conclusions: These findings support a causal role of IL-6 signaling in composite HF and HFrEF, but not HFpEF. Although the IL-6 signaling pathway plays a role in both BMI and CAD, the effect of IL-6 signaling on composite HF and HFrEF may be mediated through by CAD. Our findings demonstrate the role of IL-6 signaling in HF and its difference between HF subtypes, which may lead to more specific therapeutic targets for HF.

Abstract 13874: A Mitochondrial Polygenic Risk Score is Associated With Metabolite Levels Implicated in Heart Failure

Introduction: Heart failure (HF) is characterized by metabolic inflexibility in fuel substrate selection and results in dysregulation of downstream mitochondrial processes. Prior work has identified greater plasma concentrations of circulating long-chain acylcarnitines (LCAC) in HF. LCAC are metabolites reporting on impaired mitochondrial fatty acid catabolism and predict incident adverse events in HF. Hypothesis: We hypothesized that a polygenic risk score (PRS) of genetic variation in mitochondrially-associated genes may be associated with circulating LCAC as well as HF phenotypes. Methods: The study population consisted of 2277 European-ancestry participants from the CATHGEN (CATHeterization GENetics) cohort, consisting of sequential individuals undergoing cardiac catheterization at Duke University. Using PRSice software, a PRS was generated from variants in 1462 nuclear genes implicated in mitochondrial function; weights were derived from the HERMES HF GWAS meta-analysis. Linear regression was used to test the association between the mitochondrial function PRS and plasma metabolite levels, as well as HF phenotypes, in models adjusting for ancestry principal components and batch. Results: The analysis cohort included 515 participants with HF, with 39% females and a mean age 61.2 11.8 years. The mitochondrial PRS was associated with three LCAC: C10, C10:1 and C12:1 (nominal p-values 0.02-0.008, 18-70 variants). The PRS was not associated with prevalent cardiomyopathy (p=0.097) or HF (p=0.16). Conclusions: We have generated a focused PRS inclusive of mitochondrial nuclear genetic variants weighted on HF association and found it to be associated with relevant circulating metabolites of mitochondrial fatty acid metabolism. These results highlight the utility of a novel biology-focused PRS in cardiovascular disease traits.

Causal Association of Coffee Consumption and Total, Knee, Hip and Self-Reported Osteoarthritis: A Mendelian Randomization Study.

BackgroundThe causal association between coffee consumption and the risk of OA is limited. This study was conducted to identify the potential causal effects of coffee consumption on total, knee, hip, and self-reported OA.MethodsGenome-wide association studies (GWAS) of OA were derived from the UK Biobank, comprising 50,508 participants of European ancestry (10,083 with cases and 40,425 controls), and genetic data for specific diagnosed knee OA (4462 cases and 17,885 controls), hip OA (12,625 cases and 50,898 controls), and self-reported OA (12,658 cases and 50,898 controls). Primary and secondary genetic instruments (11 SNPs and 8 SNPs) were selected as instrumental variants from GWAS among 375,833 and 91,462 participants. Two-sample Mendelian randomization (MR) analyses were performed to test the effects of the selected single nucleotide polymorphisms (SNPs) and the OA risk. The causal effects were primarily estimated using weighted median and inverse-variance weighted method with several sensitivity analyses.ResultsThe MR analyses suggested that genetically predicted 1% increase of coffee consumption was associated with an increased risk of overall OA (OR:1.009, 95% CI:1.003-1.016), knee OA (OR:1.023, 95% CI:1.009-1.038), self-reported OA (OR:1.007, 95% CI:1.003-1.011), but not hip OA (OR: 1.012, 95%CI:0.999-1.024) using primary genetic instruments. Similar results were found when using secondary genetic instruments that genetically predicted coffee consumption (cups/day). Additionally, the sensitivity analyses for leave-one-out methods supported a robust association between exposure traits and OA.ConclusionOur findings indicate that genetically predicted coffee consumption exerts a causal effect on total, knee, and self-reported OA risk, but not at the hip. Further research is required to unravel the role of coffee consumption in OA prevention.

The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between Subtypes

BackgroundMajor depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder, but little is known about the genetic characterization of this heterogeneity. Understanding the genetic etiology of MDD can be challenging because large sample sizes are needed for gene discovery—often achieved with a trade-off in the depth of phenotyping. MethodsThe Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest publicly available depression genome-wide association study to date and subsequently used polygenic scores to investigate genetic heterogeneity across various clinical subtypes of MDD. ResultsWe increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We found that a polygenic score for depression explained 5.7% of variance in MDD liability in our sample. Finally, we found strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course, and various subtypes of MDD. ConclusionsUntil now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with the discovery of novel loci, we provide support for differential pathways to illness models that recognize the overlap with other common psychiatric disorders as well as pathophysiological differences.

Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease

SummaryNon-alcoholic fatty liver disease (NAFLD) is a complex disease linked to several chronic diseases. We aimed at identifying genetic variants associated with NAFLD and evaluating their functional consequences. We performed a genome-wide meta-analysis of 4 cohorts of electronic health record-documented NAFLD in participants of European ancestry (8,434 cases and 770,180 controls). We identify 5 potential susceptibility loci for NAFLD (located at or near GCKR, TR1B1, MAU2/TM6SF2, APOE, and PNPLA3). We also report a potentially causal effect of lower LPL expression in adipose tissue on NAFLD susceptibility and an effect of the FTO genotype on NAFLD. Positive genetic correlations between NAFLD and cardiometabolic diseases and risk factors such as body fat accumulation/distribution, lipoprotein-lipid levels, insulin resistance, and coronary artery disease and negative genetic correlations with parental lifespan, socio-economic status, and acetoacetate levels are observed. This large GWAS meta-analysis reveals insights into the genetic architecture of NAFLD.

Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids ‘not as prescribed’. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (rg = 0.64, 0.80, respectively). We also identified numerous additional genetic correlations with POU, including alcohol dependence (rg = 0.74), smoking initiation (rg = 0.63), pain relief medication intake (rg = 0.49), major depressive disorder (rg = 0.44), chronic pain (rg = 0.42), insomnia (rg = 0.39), and loneliness (rg = 0.28). Although POU was positively genetically correlated with risk-taking (rg = 0.38), conditioning POU on risk-taking did not substantially alter the magnitude or direction of these genetic correlations, suggesting that POU does not simply reflect a genetic tendency towards risky behavior. Lastly, we performed phenome- and lab-wide association analyses, which uncovered additional phenotypes that were associated with POU, including respiratory failure, insomnia, ischemic heart disease, and metabolic and blood-related biomarkers. We conclude that opioid misuse can be measured in population-based cohorts and provides a cost-effective complementary strategy for understanding the genetic basis of OUD.

Contributions of PTSD polygenic risk and environmental stress to suicidality in preadolescents

Suicidal ideation and attempts (i.e., suicidality) are complex behaviors driven by environmental stress, genetic susceptibility, and their interaction. Preadolescent suicidality is a major health problem with rising rates, yet its underlying biology is understudied. Here we studied effects of genetic stress susceptibility, approximated by the polygenic risk score (PRS) for post-traumatic-stress-disorder (PTSD), on preadolescent suicidality in participants from the Adolescent Brain Cognitive Development (ABCD) Study®. We further evaluated PTSD-PRS effects on suicidality in the presence of environmental stressors that are established suicide risk factors. Analyses included both European and African ancestry participants using PRS calculated based on summary statistics from ancestry-specific genome-wide association studies. In European ancestry participants (N = 4,619, n = 378 suicidal), PTSD-PRS was associated with preadolescent suicidality (odds ratio [OR] = 1.12, 95%CI 1–1.25, p = 0.038). Results in African ancestry participants (N = 1,334, n = 130 suicidal) showed a similar direction but were not statistically significant (OR = 1.21, 95%CI 0.93–1.57, p = 0.153). Sensitivity analyses using non-psychiatric polygenic score for height and using cross-ancestry PTSD-PRS did not reveal any association with suicidality, supporting the specificity of the association of ancestry-specific PTSD-PRS with suicidality. Environmental stressors were robustly associated with suicidality across ancestries with moderate effect size for negative life events and family conflict (OR 1.27–1.6); and with large effect size (OR ∼ 4) for sexual-orientation discrimination. When combined with environmental factors, PTSD-PRS showed marginal additive effects in explaining variability in suicidality, with no evidence for G × E interaction. Results support use of cross-phenotype PRS, specifically stress-susceptibility, as a genetic marker for suicidality risk early in the lifespan.