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Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.

Publication ,  Journal Article
Henry, A; Mo, X; Finan, C; Chaffin, MD; Speed, D; Issa, H; Denaxas, S; Ware, JS; Zheng, SL; Malarstig, A; Gratton, J; Bond, I; Roselli, C ...
Published in: Nat Genet
April 2025

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

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Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

April 2025

Volume

57

Issue

4

Start / End Page

815 / 828

Location

United States

Related Subject Headings

  • Ventricular Function, Left
  • Stroke Volume
  • Polymorphism, Single Nucleotide
  • Male
  • Humans
  • Heart Failure
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Female
  • Developmental Biology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Henry, A., Mo, X., Finan, C., Chaffin, M. D., Speed, D., Issa, H., … HERMES Consortium. (2025). Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes. Nat Genet, 57(4), 815–828. https://doi.org/10.1038/s41588-024-02064-3
Henry, Albert, Xiaodong Mo, Chris Finan, Mark D. Chaffin, Doug Speed, Hanane Issa, Spiros Denaxas, et al. “Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.Nat Genet 57, no. 4 (April 2025): 815–28. https://doi.org/10.1038/s41588-024-02064-3.
Henry A, Mo X, Finan C, Chaffin MD, Speed D, Issa H, et al. Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes. Nat Genet. 2025 Apr;57(4):815–28.
Henry, Albert, et al. “Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.Nat Genet, vol. 57, no. 4, Apr. 2025, pp. 815–28. Pubmed, doi:10.1038/s41588-024-02064-3.
Henry A, Mo X, Finan C, Chaffin MD, Speed D, Issa H, Denaxas S, Ware JS, Zheng SL, Malarstig A, Gratton J, Bond I, Roselli C, Miller D, Chopade S, Schmidt AF, Abner E, Adams L, Andersson C, Aragam KG, Ärnlöv J, Asselin G, Raja AA, Backman JD, Bartz TM, Biddinger KJ, Biggs ML, Bloom HL, Boersma E, Brandimarto J, Brown MR, Brunak S, Bruun MT, Buckbinder L, Bundgaard H, Carey DJ, Chasman DI, Chen X, Cook JP, Czuba T, de Denus S, Dehghan A, Delgado GE, Doney AS, Dörr M, Dowsett J, Dudley SC, Engström G, Erikstrup C, Esko T, Farber-Eger EH, Felix SB, Finer S, Ford I, Ghanbari M, Ghasemi S, Ghouse J, Giedraitis V, Giulianini F, Gottdiener JS, Gross S, Guðbjartsson DF, Gui H, Gutmann R, Hägg S, Haggerty CM, Hedman ÅK, Helgadottir A, Hemingway H, Hillege H, Hyde CL, Aagaard Jensen B, Jukema JW, Kardys I, Karra R, Kavousi M, Kizer JR, Kleber ME, Køber L, Koekemoer A, Kuchenbaecker K, Lai Y-P, Lanfear D, Langenberg C, Lin H, Lind L, Lindgren CM, Liu PP, London B, Lowery BD, Luan J, Lubitz SA, Magnusson P, Margulies KB, Marston NA, Martin H, März W, Melander O, Mordi IR, Morley MP, Morris AP, Morrison AC, Morton L, Nagle MW, Nelson CP, Niessner A, Niiranen T, Noordam R, Nowak C, O’Donoghue ML, Ostrowski SR, Owens AT, Palmer CNA, Paré G, Pedersen OB, Perola M, Pigeyre M, Psaty BM, Rice KM, Ridker PM, Romaine SPR, Rotter JI, Ruff CT, Sabatine MS, Sallah N, Salomaa V, Sattar N, Shalaby AA, Shekhar A, Smelser DT, Smith NL, Sørensen E, Srinivasan S, Stefansson K, Sveinbjörnsson G, Svensson P, Tammesoo M-L, Tardif J-C, Teder-Laving M, Teumer A, Thorgeirsson G, Thorsteinsdottir U, Torp-Pedersen C, Tragante V, Trompet S, Uitterlinden AG, Ullum H, van der Harst P, van Heel D, van Setten J, van Vugt M, Veluchamy A, Verschuuren M, Verweij N, Vissing CR, Völker U, Voors AA, Wallentin L, Wang Y, Weeke PE, Wiggins KL, Williams LK, Yang Y, Yu B, Zannad F, Zheng C, Genes & Health Research Team, Estonian Biobank Research Team, DBDS Genomic Consortium, Asselbergs FW, Cappola TP, Dubé M-P, Dunn ME, Lang CC, Samani NJ, Shah S, Vasan RS, Smith JG, Holm H, Ellinor PT, Hingorani AD, Wells Q, Lumbers RT, HERMES Consortium. Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes. Nat Genet. 2025 Apr;57(4):815–828.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

April 2025

Volume

57

Issue

4

Start / End Page

815 / 828

Location

United States

Related Subject Headings

  • Ventricular Function, Left
  • Stroke Volume
  • Polymorphism, Single Nucleotide
  • Male
  • Humans
  • Heart Failure
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Female
  • Developmental Biology