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

Michael G. Levin, Noah L. Tsao, Pankhuri Singhal, Chang Liu, Ha My T. Vy, Ishan Paranjpe, Joshua D. Backman, Tiffany R. Bellomo, William P. Bone, Kiran J. Biddinger, Qin Hui, Ozan Dikilitas, Benjamin A. Satterfield, Yifan Yang, Michael P. Morley, Yuki Bradford, Megan Burke, Nosheen Reza, Brian Charest, Renae L. Judy, Megan J. Puckelwartz, Hakon Hakonarson, Atlas Khan, Leah C. Kottyan, Iftikhar Kullo, Yuan Luo, Elizabeth M. McNally, Laura J. Rasmussen-Torvik, Sharlene M. Day, Ron Do, Lawrence S. Phillips, Patrick T. Ellinor, Girish N. Nadkarni, Marylyn D. Ritchie, Zoltan Arany, Thomas P. Cappola, Kenneth B. Margulies, Krishna G. Aragam, Christopher M. Haggerty, Jacob Joseph, Yan V. Sun, Benjamin F. Voight and Scott M. Damrauer ()
Additional contact information
Michael G. Levin: University of Pennsylvania
Noah L. Tsao: University of Pennsylvania Perelman School of Medicine
Pankhuri Singhal: University of Pennsylvania Perelman School of Medicine
Chang Liu: Emory University
Ha My T. Vy: Icahn School of Medicine at Mount Sinai
Ishan Paranjpe: Stanford University School of Medicine
Joshua D. Backman: Regeneron Genetics Center
Tiffany R. Bellomo: University of Pennsylvania Perelman School of Medicine
William P. Bone: University of Pennsylvania
Kiran J. Biddinger: Harvard Medical School
Qin Hui: Emory University School of Public Health
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 Perelman School of Medicine
Megan Burke: University of Pennsylvania
Nosheen Reza: University of Pennsylvania
Brian Charest: VA Boston Healthcare System
Renae L. Judy: University of Pennsylvania Perelman School of Medicine
Megan J. Puckelwartz: Northwestern University Feinberg School of Medicine
Hakon Hakonarson: The Children’s Hospital of Philadelphia
Atlas Khan: Columbia University
Leah C. Kottyan: Cincinnati Children’s Hospital Medical Center
Iftikhar Kullo: Mayo Clinic
Yuan Luo: Northwestern University
Elizabeth M. McNally: Northwestern University Feinberg School of Medicine
Laura J. Rasmussen-Torvik: Northwestern University Feinberg School of Medicine
Sharlene M. Day: University of Pennsylvania
Ron Do: Icahn School of Medicine at Mount Sinai
Lawrence S. Phillips: Atlanta VA Health Care System
Patrick T. Ellinor: Broad Institute of MIT and Harvard
Girish N. Nadkarni: Icahn School of Medicine at Mount Sinai
Marylyn D. Ritchie: University of Pennsylvania Perelman School of Medicine
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 V. Sun: Emory University School of Public Health
Benjamin F. Voight: University of Pennsylvania Perelman School of Medicine
Scott M. Damrauer: Corporal Michael J. Crescenz VA Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34216-6

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