Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes
Recommended Citation
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 Å K, 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 YP, 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 ML, Tardif JC, 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, Asselbergs FW, Cappola TP, Dubé MP, Dunn ME, Lang CC, Samani NJ, Shah S, Vasan RS, Smith JG, Holm H, Shah S, Ellinor PT, Hingorani AD, Wells Q, and Lumbers RT. Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes. Nat Genet 2025; 57(4):815-828.
Document Type
Article
Publication Date
4-1-2025
Publication Title
Nature genetics
Abstract
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.
Medical Subject Headings
Humans; Genome-Wide Association Study; Heart Failure; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Stroke Volume; Male; Female; Ventricular Function, Left
PubMed ID
40038546
ePublication
ePub ahead of print
Volume
57
Issue
4
First Page
815
Last Page
828
