👤 Krishna Aragam

Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in TTN, MYBPC3, FLNC and BAG3 using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in TTN. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing. Show less

Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, which 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-value < 5×10 Show less

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure. Show less

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. To assess the contributions of rare and common genetic variation to risk of HCM in the general population. 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. Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors. Risk of HCM. 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). 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. Show less

Pathogenic variants associated with inherited cardiomyopathy are recognized as important and clinically actionable when identified, leading some clinicians to recommend population-wide genomic screening. To determine the prevalence and clinical importance of pathogenic variants associated with inherited cardiomyopathy within the context of contemporary clinical care. This was a genetic association study of participants in Atherosclerosis in Risk Communities (ARIC), recruited from 1987 to 1989, with median follow-up of 27 years, and the UK Biobank, recruited from 2006 to 2010, with median follow-up of 10 years. ARIC participants were recruited from 4 sites across the US. UK Biobank participants were recruited from 22 sites across the UK. Participants in the US were of African and European ancestry; those in the UK were of African, East Asian, South Asian, and European ancestry. Statistical analyses were performed between August 1, 2021, and February 9, 2022. Rare genetic variants predisposing to inherited cardiomyopathy. Pathogenicity of observed DNA sequence variants in sequenced exomes of 13 genes (ACTC1, FLNC, GLA, LMNA, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2, TPM1, and TTN) associated with inherited cardiomyopathies were classified by a blinded clinical geneticist per American College of Medical Genetics recommendations. Incidence of all-cause mortality, heart failure, and atrial fibrillation were determined. Cardiac magnetic resonance imaging, echocardiography, and electrocardiogram measures were assessed in a subset of participants. A total of 9667 ARIC participants (mean [SD] age, 54.0 [5.7] years; 4232 women [43.8%]; 2658 African [27.5%] and 7009 European [72.5%] ancestry) and 49 744 UK Biobank participants (mean [SD] age, 57.1 [8.0] years; 27 142 women [54.5%]; 1006 African [2.0%], 173 East Asian [0.3%], 939 South Asian [1.9%], and 46 449 European [93.4%] European ancestry) were included in the study. Of those, 59 participants (0.61%) in ARIC and 364 participants (0.73%) in UK Biobank harbored an actionable pathogenic or likely pathogenic variant associated with dilated or hypertrophic cardiomyopathy. Carriers of these variants were not reliably identifiable by imaging. However, the presence of these variants was associated with increased risk of heart failure (hazard ratio [HR], 1.7; 95% CI, 1.1-2.8), atrial fibrillation (HR, 2.9; 95% CI, 1.9-4.5), and all-cause mortality (HR, 1.5; 95% CI, 1.1-2.2) in ARIC. Similar risk patterns were observed in the UK Biobank. Results of this genetic association study suggest that approximately 0.7% of study participants harbored a pathogenic variant associated with inherited cardiomyopathy. These variant carriers would be challenging to identify within clinical practice without genetic testing but are at increased risk for cardiovascular disease and all-cause mortality. Show less

Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3, LDLR, GCK, PKD1 and TTN. Many genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes. We identified several large effect associations for height and 18 unique genes associated with blood lipid or glucose levels. Finally, we found that between 1.0% and 2.4% of participants carried rare potentially pathogenic variants for cardiometabolic disorders. These findings may facilitate studies aimed at therapeutics and screening of these common disorders. Show less

The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Show less