Rare coding variant analysis for human diseases across biobanks and ancestries.

Large-scale sequencing has enabled unparalleled opportunities to investigate the role of rare coding variation in human phenotypic variability. Here, we present a pan-ancestry analysis of sequencing data from three large biobanks, including the All of Us research program. Using mixed-effects models, we performed gene-based rare variant testing for 601 diseases across 748,879 individuals, including 155,236 with ancestry dissimilar to European. We identified 363 significant associations, which highlighted core genes for the human disease phenome and identified potential novel associations, including UBR3 for cardiometabolic disease and YLPM1 for psychiatric disease. Pan-ancestry burden testing represented an inclusive and useful approach for discovery in diverse datasets, although we also highlight the importance of ancestry-specific sensitivity analyses in this setting. Finally, we found that effect sizes for rare protein-disrupting variants were concordant between samples similar to European ancestry and other genetic ancestries (ßDeming = 0.7-1.0). Our results have implications for multi-ancestry and cross-biobank approaches in sequencing association studies for human disease.

Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass.

Left ventricular mass is a risk marker for cardiovascular events, and may indicate an underlying cardiomyopathy. Cardiac magnetic resonance is the gold-standard for left ventricular mass estimation, but is challenging to obtain at scale. Here, we use deep learning to enable genome-wide association study of cardiac magnetic resonance-derived left ventricular mass indexed to body surface area within 43,230 UK Biobank participants. We identify 12 genome-wide associations (1 known at TTN and 11 novel for left ventricular mass), implicating genes previously associated with cardiac contractility and cardiomyopathy. Cardiac magnetic resonance-derived indexed left ventricular mass is associated with incident dilated and hypertrophic cardiomyopathies, and implantable cardioverter-defibrillator implant. An indexed left ventricular mass polygenic risk score ≥90th percentile is also associated with incident implantable cardioverter-defibrillator implant in separate UK Biobank (hazard ratio 1.22, 95% CI 1.05-1.44) and Mass General Brigham (hazard ratio 1.75, 95% CI 1.12-2.74) samples. Here, we perform a genome-wide association study of cardiac magnetic resonance-derived indexed left ventricular mass to identify 11 novel variants and demonstrate that cardiac magnetic resonance-derived and genetically predicted indexed left ventricular mass are associated with incident cardiomyopathy.

Common- and rare-variant genetic architecture of heart failure across the allele frequency spectrum.

Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, that affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, where rare genetic variants have been linked to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multiple populations including 207,346 individuals with HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (p < 5×10-8). Signals at newly identified common-variant loci include coding variants in Mendelian cardiomyopathy genes (MYBPC3, BAG3), as well as regulators of lipoprotein (LPL) and glucose metabolism (GIPR, GLP1R), and are enriched in cardiac, muscle, nerve, and vascular tissues, as well as myocyte and adipocyte cell types. Gene burden studies across three biobanks (PMBB, UKB, AOU) including 27,208 individuals with HF and 349,126 without uncover exome-wide significant (p < 3.15×10-6) associations for HF and rare predicted loss-of-function (pLoF) variants in TTN, MYBPC3, FLNC, and BAG3. Total burden heritability of rare coding variants (2.2%, 95% CI 0.99-3.5%) is highly concentrated in a small set of Mendelian cardiomyopathy genes, and is lower than heritability attributable to common variants (4.3%, 95% CI 3.9-4.7%) which is more diffusely spread throughout the genome. Finally, we demonstrate that common-variant background, in the form of a polygenic risk score (PRS), significantly modifies the risk of HF among carriers of pathogenic truncating variants in the Mendelian cardiomyopathy gene TTN. These findings suggest a significant polygenic component to HF exists that is not captured by current clinical genetic testing.

Rare and Common Genetic Variation Underlying the Risk of Hypertrophic Cardiomyopathy in a National Biobank.

Importance: Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recently been implicated in disease pathogenesis. Objective: To assess the contributions of rare and common genetic variation to risk of HCM in the general population. Design, Setting, and Participants: This cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022. Exposures: Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors. Main Outcomes and Measures: Risk of HCM. Results: The primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics [ACMG]) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87). Conclusions and Relevance: Both rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.

Association of Habitual Alcohol Intake With Risk of Cardiovascular Disease.

Importance: Observational studies have consistently proposed cardiovascular benefits associated with light alcohol consumption, while recent genetic analyses (ie, mendelian randomization studies) have suggested a possible causal link between alcohol intake and increased risk of cardiovascular disease. However, traditional approaches to genetic epidemiology assume a linear association and thus have not fully evaluated dose-response estimates of risk across different levels of alcohol intake. Objectives: To assess the association of habitual alcohol intake with cardiovascular disease risk and to evaluate the direction and relative magnitude of cardiovascular risk associated with different amounts of alcohol consumption. Design, Setting, and Participants: This cohort study used the UK Biobank (2006-2010, follow-up until 2016) to examine confounding in epidemiologic associations between alcohol intake and cardiovascular diseases. Using both traditional (ie, linear) and nonlinear mendelian randomization, potential associations between alcohol consumption and cardiovascular diseases (eg, hypertension and coronary artery disease) as well as corresponding association shapes were assessed. Data analysis was conducted from July 2019 to January 2022. Exposures: Genetic predisposition to alcohol intake. Main Outcomes and Measures: The association between alcohol consumption and cardiovascular diseases, including hypertension, coronary artery disease, myocardial infarction, stroke, heart failure, and atrial fibrillation. Results: This study included 371 463 participants (mean [SD] age, 57.0 [7.9] years; 172 400 [46%] men), who consumed a mean (SD) 9.2 (10.6) standard drinks per week. Overall, 121 708 participants (33%) had hypertension. Light to moderate alcohol consumption was associated with healthier lifestyle factors, adjustment for which attenuated the cardioprotective epidemiologic associations with modest intake. In linear mendelian randomization analyses, a 1-SD increase in genetically predicted alcohol consumption was associated with 1.3-fold (95% CI, 1.2-1.4) higher risk of hypertension (P < .001) and 1.4-fold (95% CI, 1.1-1.8) higher risk of coronary artery disease (P = .006). Nonlinear mendelian randomization analyses suggested nonlinear associations between alcohol consumption and both hypertension and coronary artery disease: light alcohol intake was associated with minimal increases in cardiovascular risk, whereas heavier consumption was associated with exponential increases in risk of both clinical and subclinical cardiovascular disease. Conclusions and Relevance: In this cohort study, coincident, favorable lifestyle factors attenuated the observational benefits of modest alcohol intake. Genetic epidemiology suggested that alcohol consumption of all amounts was associated with increased cardiovascular risk, but marked risk differences exist across levels of intake, including those accepted by current national guidelines.

Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure.

Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets.