Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Levin MG

PROVIDER: S-EPMC9663424 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Levin Michael G MG Tsao Noah L NL Singhal Pankhuri P Liu Chang C Vy Ha My T HMT Paranjpe Ishan I Backman Joshua D JD Bellomo Tiffany R TR Bone William P WP Biddinger Kiran J KJ Hui Qin Q Dikilitas Ozan O Satterfield Benjamin A BA Yang Yifan Y Morley Michael P MP Bradford Yuki Y Burke Megan M Reza Nosheen N Charest Brian B Judy Renae L RL Puckelwartz Megan J MJ Hakonarson Hakon H Khan Atlas A Kottyan Leah C LC Kullo Iftikhar I Luo Yuan Y McNally Elizabeth M EM Rasmussen-Torvik Laura J LJ Day Sharlene M SM Do Ron R Phillips Lawrence S LS Ellinor Patrick T PT Nadkarni Girish N GN Ritchie Marylyn D MD Arany Zoltan Z Cappola Thomas P TP Margulies Kenneth B KB Aragam Krishna G KG Haggerty Christopher M CM Joseph Jacob J Sun Yan V YV Voight Benjamin F BF Damrauer Scott M SM

Nature communications 20221114 1

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 ass ...[more]

PMID: 36376295

Similar Datasets

Project description: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.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets