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

Regeneron Genetics Center

doi:10.1038/s41467-022-34216-6

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

Regeneron Genetics Center

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

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.

Original language	English (US)
Article number	6914
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34216-6
State	Published - Dec 2022

Funding

The authors thank the participants of the contributing biobanks and consortia. M.G.L. is supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, the NIH/NHLBI National Research Service Award postdoctoral fellowship (T32HL007843), and the Measey Foundation. B.F.V. is supported by the NIH/NIDDK (DK126194 and DK101478). S.M Damrauer is supported by US Department of Veterans Affairs grant IK2-CX001780. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award I01-CX001737 (PI: Phillips) and I01-BX004821 (PI: Wilson/Cho). This publication does not represent the views of the Department of Veterans Affairs or the US government. N.R. is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001879. E.M.M. is supported by NIH HL128075, the American Heart Association Strategically Funded Research Network on Arrhythmias and Sudden Cardiac Death, and the Leducq Foundation. Z.A. is supported by the NIH/NHLBI (HL152446). K.B.M., T.P.C., and the MAGNET Consortium are supported by the NIH/NHLBI (R01 HL105993). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Members of Regeneron Genetics Center are listed within the Supplementary materials. J.D.B. is a full-time employee of Regeneron Genetics Center. E.M.M. consults for Amgen, Avidity, AstraZeneca, Cytokinetics, Janssen, PepGen, Pfizer, Stealth BioTherapeutics, Tenaya Therapeutics, and is a founder of Ikaika Therapeutics. S.M. Damrauer receives research support from RenalytixAI and in-kind research support from Novo Nordisk, as well as personal consulting fees from Calico Labs. The remaining authors declare no competing interests. The authors thank the participants of the contributing biobanks and consortia. M.G.L. is supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, the NIH/NHLBI National Research Service Award postdoctoral fellowship (T32HL007843), and the Measey Foundation. B.F.V. is supported by the NIH/NIDDK (DK126194 and DK101478). S.M Damrauer is supported by US Department of Veterans Affairs grant IK2-CX001780. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award I01-CX001737 (PI: Phillips) and I01-BX004821 (PI: Wilson/Cho). This publication does not represent the views of the Department of Veterans Affairs or the US government. N.R. is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001879. E.M.M. is supported by NIH HL128075, the American Heart Association Strategically Funded Research Network on Arrhythmias and Sudden Cardiac Death, and the Leducq Foundation. Z.A. is supported by the NIH/NHLBI (HL152446). K.B.M., T.P.C., and the MAGNET Consortium are supported by the NIH/NHLBI (R01 HL105993). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Members of Regeneron Genetics Center are listed within the Supplementary materials.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-022-34216-6

Cite this

@article{3edcf95e2a8049eda652290cbaa7c732,

title = "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.",

author = "{Regeneron Genetics Center} and Levin, {Michael G.} and Tsao, {Noah L.} and Pankhuri Singhal and Chang Liu and Vy, {Ha My T.} and Ishan Paranjpe and Backman, {Joshua D.} and Bellomo, {Tiffany R.} and Bone, {William P.} and Biddinger, {Kiran J.} and Qin Hui and Ozan Dikilitas and Satterfield, {Benjamin A.} and Yifan Yang and Morley, {Michael P.} and Yuki Bradford and Megan Burke and Nosheen Reza and Brian Charest and Judy, {Renae L.} and Puckelwartz, {Megan J.} and Hakon Hakonarson and Atlas Khan and Kottyan, {Leah C.} and Iftikhar Kullo and Yuan Luo and McNally, {Elizabeth M.} and Rasmussen-Torvik, {Laura J.} and Day, {Sharlene M.} and Ron Do and Phillips, {Lawrence S.} and Ellinor, {Patrick T.} and Nadkarni, {Girish N.} and Ritchie, {Marylyn D.} and Zoltan Arany and Cappola, {Thomas P.} and Margulies, {Kenneth B.} and Aragam, {Krishna G.} and Haggerty, {Christopher M.} and Jacob Joseph and Sun, {Yan V.} and Voight, {Benjamin F.} and Damrauer, {Scott M.}",

note = "Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-34216-6",

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure

AU - Regeneron Genetics Center

AU - Levin, Michael G.

AU - Tsao, Noah L.

AU - Singhal, Pankhuri

AU - Liu, Chang

AU - Vy, Ha My T.

AU - Paranjpe, Ishan

AU - Backman, Joshua D.

AU - Bellomo, Tiffany R.

AU - Bone, William P.

AU - Biddinger, Kiran J.

AU - Hui, Qin

AU - Dikilitas, Ozan

AU - Satterfield, Benjamin A.

AU - Yang, Yifan

AU - Morley, Michael P.

AU - Bradford, Yuki

AU - Burke, Megan

AU - Reza, Nosheen

AU - Charest, Brian

AU - Judy, Renae L.

AU - Puckelwartz, Megan J.

AU - Hakonarson, Hakon

AU - Khan, Atlas

AU - Kottyan, Leah C.

AU - Kullo, Iftikhar

AU - Luo, Yuan

AU - McNally, Elizabeth M.

AU - Rasmussen-Torvik, Laura J.

AU - Day, Sharlene M.

AU - Do, Ron

AU - Phillips, Lawrence S.

AU - Ellinor, Patrick T.

AU - Nadkarni, Girish N.

AU - Ritchie, Marylyn D.

AU - Arany, Zoltan

AU - Cappola, Thomas P.

AU - Margulies, Kenneth B.

AU - Aragam, Krishna G.

AU - Haggerty, Christopher M.

AU - Joseph, Jacob

AU - Sun, Yan V.

AU - Voight, Benjamin F.

AU - Damrauer, Scott M.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85141958522&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85141958522&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-34216-6

DO - 10.1038/s41467-022-34216-6

M3 - Article

C2 - 36376295

AN - SCOPUS:85141958522

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 6914

ER -

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this