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

• Authors: Michael G Levin, University of Pennsylvania; Noah L Tsao, University of Pennsylvania; Pankhuri Singhal, University of Pennsylvania; Chang Liu, Emory University; Ha My T Vy, Icahn School of Medicine at Mount Sinai; Ishan Paranjpe, Stanford University; Joshua D Backman, Regeneron Genetics Center; Tiffany R Bellomo, University of Pennsylvania; William P Bone, University of Pennsylvania; Kiran J Biddinger, Harvard Medical School; Qin Hui, Emory University; Ozan Dikilitas, Mayo Clinic; Benjamin A Satterfield, Mayo Clinic; Yifan Yang, University of Pennsylvania; Michael P Morley, University of Pennsylvania; Yuki Bradford, University of Pennsylvania; Megan Burke, University of Pennsylvania; Nosheen Reza, University of Pennsylvania; Brian Charest, VA Boston Healthcare System; Renae L Judy, University of Pennsylvania; Megan J Puckelwartz, Northwestern University; Hakon Hakonarson, Childrens Hospital of Philadelphia; Atlas Khan, Columbia University; Leah C Kottyan, Cincinnati Children’s Hospital Medical Center; Iftikhar Kullo, Mayo Clinic, Rochester; Yuan Luo, Northwestern University; Elizabeth M McNally, Northwestern University; Laura J Rasmussen-Torvik, Northwestern University; Sharlene M Day, University of Pennsylvania; Ron Do, Icahn School of Medicine at Mount Sinai; Lawrence Phillips, Emory University; Patrick T Ellinor, Broad Institute of MIT and Harvard, Cambridge; Girish N Nadkarni, Icahn School of Medicine at Mount Sinai; Marylyn D Ritchie, University of Pennsylvania; Zoltan Arany, University of Pennsylvania; Thomas P Cappola, University of Pennsylvania; Kenneth B Margulies, University of Pennsylvania; Krishna G Aragam, Harvard Medical School; Christopher M Haggerty, Geisinger; Jacob Joseph, VA Boston Healthcare System; Yan Sun, Emory University; Benjamin F Voight, University of Pennsylvania; Scott M Damrauer, Corporal Michael J. Crescenz VA Medical Center
• Journal Title: NATURE COMMUNICATIONS
• Volume: Volume 13, Number 1
• Publisher: NATURE PORTFOLIO | 2022-11-14, Pages 6914-6914
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41467-022-34216-6
• Subjects: Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; RISK; METAANALYSIS; DYSFUNCTION; METABOLISM; CARDIOLOGY; DELETION; GROWTH; SET

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.