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

Albert Henry; Xiaodong Mo; Chris Finan; Mark D Chaffin; Doug Speed; Hanane Issa; Spiros Denaxas; James S Ware; Sean L Zheng; Anders Malarstig; Jasmine Gratton; Isabelle Bond; Carolina Roselli; David Miller; Sandesh Chopade; A Floriaan Schmidt; Erik Abner; Lance Adams; Charlotte Andersson; Krishna G Aragam; Johan Ärnlöv; Geraldine Asselin; Anna Axelsson Raja; Joshua D Backman; Traci M Bartz; Kiran J Biddinger; Mary L Biggs; Heather L Bloom; Eric Boersma; Jeffrey Brandimarto; Michael R Brown; Søren Brunak; Mie Topholm Bruun; Leonard Buckbinder; Henning Bundgaard; David J Carey; Daniel I Chasman; Xing Chen; James P Cook; Tomasz Czuba; Simon de Denus; Abbas Dehghan; Graciela E Delgado; Alexander S Doney; Marcus Dörr; Joseph Dowsett; Samuel C Dudley; Gunnar Engström; Christian Erikstrup; Tõnu Esko; Eric H Farber-Eger; Stephan B Felix; Sarah Finer; Ian Ford; Mohsen Ghanbari; Sahar Ghasemi; Jonas Ghouse; Vilmantas Giedraitis; Franco Giulianini; John S Gottdiener; Stefan Gross; Daníel F Guðbjartsson; Hongsheng Gui; Rebecca Gutmann; Sara Hägg; Christopher M Haggerty; Åsa K Hedman; Anna Helgadottir; Harry Hemingway; Hans Hillege; Craig L Hyde; Bitten Aagaard Jensen; J Wouter Jukema; Isabella Kardys; Ravi Karra; Maryam Kavousi; Jorge R Kizer; Marcus E Kleber; Lars Køber; Andrea Koekemoer; Karoline Kuchenbaecker; Yi-Pin Lai; David Lanfear; Claudia Langenberg; Honghuang Lin; Lars Lind; Cecilia M Lindgren; Peter P Liu; Barry London; Brandon D Lowery; Jian'an Luan; Steven A Lubitz; Patrik Magnusson; Kenneth B Margulies; Nicholas A Marston; Hilary Martin; Winfried März; Olle Melander; Ify R Mordi; Michael P Morley; Andrew P Morris; Alanna C Morrison; Lori Morton; Michael W Nagle; Christopher P Nelson; Alexander Niessner; Teemu Niiranen; Raymond Noordam; Christoph Nowak; Michelle L O'Donoghue; Sisse Rye Ostrowski; Anjali T Owens; Colin N A Palmer; Guillaume Paré; Ole Birger Pedersen; Markus Perola; Marie Pigeyre; Bruce M Psaty; Kenneth M Rice; Paul M Ridker; Simon P R Romaine; Jerome I Rotter; Christian T Ruff; Marc S Sabatine; Neneh Sallah; Veikko Salomaa; Naveed Sattar; Alaa A Shalaby; Akshay Shekhar; Diane T Smelser; Nicholas L Smith; Erik Sørensen; Sundararajan Srinivasan; Kari Stefansson; Garðar Sveinbjörnsson; Per Svensson; Mari-Liis Tammesoo; Jean-Claude Tardif; Maris Teder-Laving; Alexander Teumer; Guðmundur Thorgeirsson; Unnur Thorsteinsdottir; Christian Torp-Pedersen; Vinicius Tragante; Stella Trompet; Andre G Uitterlinden; Henrik Ullum; Pim van der Harst; David van Heel; Jessica van Setten; Marion van Vugt; Abirami Veluchamy; Monique Verschuuren; Niek Verweij; Christoffer Rasmus Vissing; Uwe Völker; Adriaan A Voors; Lars Wallentin; Yunzhang Wang; Peter E Weeke; Kerri L Wiggins; L Keoki Williams; Yifan Yang; Bing Yu; Faiez Zannad; Chaoqun Zheng; Genes & Health Research Team; Estonian Biobank Research Team; DBDS Genomic Consortium; Folkert W Asselbergs; Thomas P Cappola; Marie-Pierre Dubé; Michael E Dunn; Chim C Lang; Nilesh J Samani; Svati Shah; Ramachandran S Vasan; J Gustav Smith; Hilma Holm; Sonia Shah; Patrick T Ellinor; Aroon D Hingorani; Quinn Wells; R Thomas Lumbers; HERMES Consortium

doi:10.1038/s41588-024-02064-3

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

Albert Henry, Xiaodong Mo, Chris Finan, Mark D Chaffin, Doug Speed, Hanane Issa, Spiros Denaxas, James S Ware, Sean L Zheng, Anders Malarstig, Jasmine Gratton, Isabelle Bond, Carolina Roselli, David Miller, Sandesh Chopade, A Floriaan Schmidt, Erik Abner, Lance Adams, Charlotte Andersson, Krishna G AragamJohan Ärnlöv, Geraldine Asselin, Anna Axelsson Raja, Joshua D Backman, Traci M Bartz, Kiran J Biddinger, Mary L Biggs, Heather L Bloom, Eric Boersma, Jeffrey Brandimarto, Michael R Brown, Søren Brunak, Mie Topholm Bruun, Leonard Buckbinder, Henning Bundgaard, David J Carey, Daniel I Chasman, Xing Chen, James P Cook, Tomasz Czuba, Simon de Denus, Abbas Dehghan, Graciela E Delgado, Alexander S Doney, Marcus Dörr, Joseph Dowsett, Samuel C Dudley, Gunnar Engström, Christian Erikstrup, Tõnu Esko, Eric H Farber-Eger, Stephan B Felix, Sarah Finer, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Jonas Ghouse, Vilmantas Giedraitis, Franco Giulianini, John S Gottdiener, Stefan Gross, Daníel F Guðbjartsson, Hongsheng Gui, Rebecca Gutmann, Sara Hägg, Christopher M Haggerty, Åsa K Hedman, Anna Helgadottir, Harry Hemingway, Hans Hillege, Craig L Hyde, Bitten Aagaard Jensen, J Wouter Jukema, Isabella Kardys, Ravi Karra, Maryam Kavousi, Jorge R Kizer, Marcus E Kleber, Lars Køber, Andrea Koekemoer, Karoline Kuchenbaecker, Yi-Pin Lai, David Lanfear, Claudia Langenberg, Honghuang Lin, Lars Lind, Cecilia M Lindgren, Peter P Liu, Barry London, Brandon D Lowery, Jian'an Luan, Steven A Lubitz, Patrik Magnusson, Kenneth B Margulies, Nicholas A Marston, Hilary Martin, Winfried März, Olle Melander, Ify R Mordi, Michael P Morley, Andrew P Morris, Alanna C Morrison, Lori Morton, Michael W Nagle, Christopher P Nelson, Alexander Niessner, Teemu Niiranen, Raymond Noordam, Christoph Nowak, Michelle L O'Donoghue, Sisse Rye Ostrowski, Anjali T Owens, Colin N A Palmer, Guillaume Paré, Ole Birger Pedersen, Markus Perola, Marie Pigeyre, Bruce M Psaty, Kenneth M Rice, Paul M Ridker, Simon P R Romaine, Jerome I Rotter, Christian T Ruff, Marc S Sabatine, Neneh Sallah, Veikko Salomaa, Naveed Sattar, Alaa A Shalaby, Akshay Shekhar, Diane T Smelser, Nicholas L Smith, Erik Sørensen, Sundararajan Srinivasan, Kari Stefansson, Garðar Sveinbjörnsson, Per Svensson, Mari-Liis Tammesoo, Jean-Claude Tardif, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Vinicius Tragante, Stella Trompet, Andre G Uitterlinden, Henrik Ullum, Pim van der Harst, David van Heel, Jessica van Setten, Marion van Vugt, Abirami Veluchamy, Monique Verschuuren, Niek Verweij, Christoffer Rasmus Vissing, Uwe Völker, Adriaan A Voors, Lars Wallentin, Yunzhang Wang, Peter E Weeke, Kerri L Wiggins, L Keoki Williams, Yifan Yang, Bing Yu, Faiez Zannad, Chaoqun Zheng, Genes & Health Research Team, Estonian Biobank Research Team, DBDS Genomic Consortium, Folkert W Asselbergs, Thomas P Cappola, Marie-Pierre Dubé, Michael E Dunn, Chim C Lang, Nilesh J Samani, Svati Shah, Ramachandran S Vasan, J Gustav Smith, Hilma Holm, Sonia Shah, Patrick T Ellinor, Aroon D Hingorani, Quinn Wells, R Thomas Lumbers^*, HERMES Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

1 Citation (Scopus)

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.

Original language	English
Article number	163
Journal	Nature Genetics
Volume	57
Issue number	4
Pages (from-to)	815-828
Number of pages	14
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-024-02064-3
Publication status	Published - Apr 2025

Bibliographical note

Keywords

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

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Henry et al. (2025). Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypesFinal published version, 14.8 MBLicence: CC BY 4.0

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Cite this

Henry, A., Mo, X., Finan, C., Chaffin, M. D., Speed, D., Issa, H., Denaxas, S., Ware, J. S., Zheng, S. L., Malarstig, A., Gratton, J., Bond, I., Roselli, C., Miller, D., Chopade, S., Schmidt, A. F., Abner, E., Adams, L., Andersson, C., ... HERMES Consortium (2025). Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes. Nature Genetics, 57(4), 815-828. Article 163. https://doi.org/10.1038/s41588-024-02064-3

@article{1a93bc6c51bf4b189a327d96a01787e0,

title = "Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes",

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.",

keywords = "Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Failure/genetics, Humans, Male, Polymorphism, Single Nucleotide, Stroke Volume/genetics, Ventricular Function, Left/genetics",

author = "Albert Henry and Xiaodong Mo and Chris Finan and Chaffin, {Mark D} and Doug Speed and Hanane Issa and Spiros Denaxas and Ware, {James S} and Zheng, {Sean L} and Anders Malarstig and Jasmine Gratton and Isabelle Bond and Carolina Roselli and David Miller and Sandesh Chopade and Schmidt, {A Floriaan} and Erik Abner and Lance Adams and Charlotte Andersson and Aragam, {Krishna G} and Johan {\"A}rnl{\"o}v and Geraldine Asselin and Raja, {Anna Axelsson} and Backman, {Joshua D} and Bartz, {Traci M} and Biddinger, {Kiran J} and Biggs, {Mary L} and Bloom, {Heather L} and Eric Boersma and Jeffrey Brandimarto and Brown, {Michael R} and S{\o}ren Brunak and Bruun, {Mie Topholm} and Leonard Buckbinder and Henning Bundgaard and Carey, {David J} and Chasman, {Daniel I} and Xing Chen and Cook, {James P} and Tomasz Czuba and {de Denus}, Simon and Abbas Dehghan and Delgado, {Graciela E} and Doney, {Alexander S} and Marcus D{\"o}rr and Joseph Dowsett and Dudley, {Samuel C} and Gunnar Engstr{\"o}m and Christian Erikstrup and T{\~o}nu Esko and Farber-Eger, {Eric H} and Felix, {Stephan B} and Sarah Finer and Ian Ford and Mohsen Ghanbari and Sahar Ghasemi and Jonas Ghouse and Vilmantas Giedraitis and Franco Giulianini and Gottdiener, {John S} and Stefan Gross and Gu{\dh}bjartsson, {Dan{\'i}el F} and Hongsheng Gui and Rebecca Gutmann and Sara H{\"a}gg and Haggerty, {Christopher M} and Hedman, {{\AA}sa K} and Anna Helgadottir and Harry Hemingway and Hans Hillege and Hyde, {Craig L} and {Aagaard Jensen}, Bitten and Jukema, {J Wouter} and Isabella Kardys and Ravi Karra and Maryam Kavousi and Kizer, {Jorge R} and Kleber, {Marcus E} and Lars K{\o}ber and Andrea Koekemoer and Karoline Kuchenbaecker and Yi-Pin Lai and David Lanfear and Claudia Langenberg and Honghuang Lin and Lars Lind and Lindgren, {Cecilia M} and Liu, {Peter P} and Barry London and Lowery, {Brandon D} and Jian'an Luan and Lubitz, {Steven A} and Patrik Magnusson and Margulies, {Kenneth B} and Marston, {Nicholas A} and Hilary Martin and Winfried M{\"a}rz and Olle Melander and Mordi, {Ify R} and Morley, {Michael P} and Morris, {Andrew P} and Morrison, {Alanna C} and Lori Morton and Nagle, {Michael W} and Nelson, {Christopher P} and Alexander Niessner and Teemu Niiranen and Raymond Noordam and Christoph Nowak and O'Donoghue, {Michelle L} and Ostrowski, {Sisse Rye} and Owens, {Anjali T} and Palmer, {Colin N A} and Guillaume Par{\'e} and Pedersen, {Ole Birger} and Markus Perola and Marie Pigeyre and Psaty, {Bruce M} and Rice, {Kenneth M} and Ridker, {Paul M} and Romaine, {Simon P R} and Rotter, {Jerome I} and Ruff, {Christian T} and Sabatine, {Marc S} and Neneh Sallah and Veikko Salomaa and Naveed Sattar and Shalaby, {Alaa A} and Akshay Shekhar and Smelser, {Diane T} and Smith, {Nicholas L} and Erik S{\o}rensen and Sundararajan Srinivasan and Kari Stefansson and Gar{\dh}ar Sveinbj{\"o}rnsson and Per Svensson and Mari-Liis Tammesoo and Jean-Claude Tardif and Maris Teder-Laving and Alexander Teumer and Gu{\dh}mundur Thorgeirsson and Unnur Thorsteinsdottir and Christian Torp-Pedersen and Vinicius Tragante and Stella Trompet and Uitterlinden, {Andre G} and Henrik Ullum and {van der Harst}, Pim and {van Heel}, David and {van Setten}, Jessica and {van Vugt}, Marion and Abirami Veluchamy and Monique Verschuuren and Niek Verweij and Vissing, {Christoffer Rasmus} and Uwe V{\"o}lker and Voors, {Adriaan A} and Lars Wallentin and Yunzhang Wang and Weeke, {Peter E} and Wiggins, {Kerri L} and Williams, {L Keoki} and Yifan Yang and Bing Yu and Faiez Zannad and Chaoqun Zheng and {Genes & Health Research Team} and {Estonian Biobank Research Team} and {DBDS Genomic Consortium} and Asselbergs, {Folkert W} and Cappola, {Thomas P} and Marie-Pierre Dub{\'e} and Dunn, {Michael E} and Lang, {Chim C} and Samani, {Nilesh J} and Svati Shah and Vasan, {Ramachandran S} and Smith, {J Gustav} and Hilma Holm and Sonia Shah and Ellinor, {Patrick T} and Hingorani, {Aroon D} and Quinn Wells and Lumbers, {R Thomas} and {HERMES Consortium}",

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = apr,

doi = "10.1038/s41588-024-02064-3",

language = "English",

volume = "57",

pages = "815--828",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "4",

}

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, Shah, S, Ellinor, PT, Hingorani, AD, Wells, Q, Lumbers, RT & HERMES Consortium 2025, 'Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes', Nature Genetics, vol. 57, no. 4, 163, pp. 815-828. https://doi.org/10.1038/s41588-024-02064-3

TY - JOUR

T1 - Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes

AU - Henry, Albert

AU - Mo, Xiaodong

AU - Finan, Chris

AU - Chaffin, Mark D

AU - Speed, Doug

AU - Issa, Hanane

AU - Denaxas, Spiros

AU - Ware, James S

AU - Zheng, Sean L

AU - Malarstig, Anders

AU - Gratton, Jasmine

AU - Bond, Isabelle

AU - Roselli, Carolina

AU - Miller, David

AU - Chopade, Sandesh

AU - Schmidt, A Floriaan

AU - Abner, Erik

AU - Adams, Lance

AU - Andersson, Charlotte

AU - Aragam, Krishna G

AU - Ärnlöv, Johan

AU - Asselin, Geraldine

AU - Raja, Anna Axelsson

AU - Backman, Joshua D

AU - Bartz, Traci M

AU - Biddinger, Kiran J

AU - Biggs, Mary L

AU - Bloom, Heather L

AU - Boersma, Eric

AU - Brandimarto, Jeffrey

AU - Brown, Michael R

AU - Brunak, Søren

AU - Bruun, Mie Topholm

AU - Buckbinder, Leonard

AU - Bundgaard, Henning

AU - Carey, David J

AU - Chasman, Daniel I

AU - Chen, Xing

AU - Cook, James P

AU - Czuba, Tomasz

AU - de Denus, Simon

AU - Dehghan, Abbas

AU - Delgado, Graciela E

AU - Doney, Alexander S

AU - Dörr, Marcus

AU - Dowsett, Joseph

AU - Dudley, Samuel C

AU - Engström, Gunnar

AU - Erikstrup, Christian

AU - Esko, Tõnu

AU - Farber-Eger, Eric H

AU - Felix, Stephan B

AU - Finer, Sarah

AU - Ford, Ian

AU - Ghanbari, Mohsen

AU - Ghasemi, Sahar

AU - Ghouse, Jonas

AU - Giedraitis, Vilmantas

AU - Giulianini, Franco

AU - Gottdiener, John S

AU - Gross, Stefan

AU - Guðbjartsson, Daníel F

AU - Gui, Hongsheng

AU - Gutmann, Rebecca

AU - Hägg, Sara

AU - Haggerty, Christopher M

AU - Hedman, Åsa K

AU - Helgadottir, Anna

AU - Hemingway, Harry

AU - Hillege, Hans

AU - Hyde, Craig L

AU - Aagaard Jensen, Bitten

AU - Jukema, J Wouter

AU - Kardys, Isabella

AU - Karra, Ravi

AU - Kavousi, Maryam

AU - Kizer, Jorge R

AU - Kleber, Marcus E

AU - Køber, Lars

AU - Koekemoer, Andrea

AU - Kuchenbaecker, Karoline

AU - Lai, Yi-Pin

AU - Lanfear, David

AU - Langenberg, Claudia

AU - Lin, Honghuang

AU - Lind, Lars

AU - Lindgren, Cecilia M

AU - Liu, Peter P

AU - London, Barry

AU - Lowery, Brandon D

AU - Luan, Jian'an

AU - Lubitz, Steven A

AU - Magnusson, Patrik

AU - Margulies, Kenneth B

AU - Marston, Nicholas A

AU - Martin, Hilary

AU - März, Winfried

AU - Melander, Olle

AU - Mordi, Ify R

AU - Morley, Michael P

AU - Morris, Andrew P

AU - Morrison, Alanna C

AU - Morton, Lori

AU - Nagle, Michael W

AU - Nelson, Christopher P

AU - Niessner, Alexander

AU - Niiranen, Teemu

AU - Noordam, Raymond

AU - Nowak, Christoph

AU - O'Donoghue, Michelle L

AU - Ostrowski, Sisse Rye

AU - Owens, Anjali T

AU - Palmer, Colin N A

AU - Paré, Guillaume

AU - Pedersen, Ole Birger

AU - Perola, Markus

AU - Pigeyre, Marie

AU - Psaty, Bruce M

AU - Rice, Kenneth M

AU - Ridker, Paul M

AU - Romaine, Simon P R

AU - Rotter, Jerome I

AU - Ruff, Christian T

AU - Sabatine, Marc S

AU - Sallah, Neneh

AU - Salomaa, Veikko

AU - Sattar, Naveed

AU - Shalaby, Alaa A

AU - Shekhar, Akshay

AU - Smelser, Diane T

AU - Smith, Nicholas L

AU - Sørensen, Erik

AU - Srinivasan, Sundararajan

AU - Stefansson, Kari

AU - Sveinbjörnsson, Garðar

AU - Svensson, Per

AU - Tammesoo, Mari-Liis

AU - Tardif, Jean-Claude

AU - Teder-Laving, Maris

AU - Teumer, Alexander

AU - Thorgeirsson, Guðmundur

AU - Thorsteinsdottir, Unnur

AU - Torp-Pedersen, Christian

AU - Tragante, Vinicius

AU - Trompet, Stella

AU - Uitterlinden, Andre G

AU - Ullum, Henrik

AU - van der Harst, Pim

AU - van Heel, David

AU - van Setten, Jessica

AU - van Vugt, Marion

AU - Veluchamy, Abirami

AU - Verschuuren, Monique

AU - Verweij, Niek

AU - Vissing, Christoffer Rasmus

AU - Völker, Uwe

AU - Voors, Adriaan A

AU - Wallentin, Lars

AU - Wang, Yunzhang

AU - Weeke, Peter E

AU - Wiggins, Kerri L

AU - Williams, L Keoki

AU - Yang, Yifan

AU - Yu, Bing

AU - Zannad, Faiez

AU - Zheng, Chaoqun

AU - Genes & Health Research Team

AU - Estonian Biobank Research Team

AU - DBDS Genomic Consortium

AU - Asselbergs, Folkert W

AU - Cappola, Thomas P

AU - Dubé, Marie-Pierre

AU - Dunn, Michael E

AU - Lang, Chim C

AU - Samani, Nilesh J

AU - Shah, Svati

AU - Vasan, Ramachandran S

AU - Smith, J Gustav

AU - Holm, Hilma

AU - Shah, Sonia

AU - Ellinor, Patrick T

AU - Hingorani, Aroon D

AU - Wells, Quinn

AU - Lumbers, R Thomas

AU - HERMES Consortium

PY - 2025/4

Y1 - 2025/4

N2 - 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.

AB - 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.

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Heart Failure/genetics

KW - Humans

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Stroke Volume/genetics

KW - Ventricular Function, Left/genetics

U2 - 10.1038/s41588-024-02064-3

DO - 10.1038/s41588-024-02064-3

M3 - Journal article

C2 - 40038546

SN - 1061-4036

VL - 57

SP - 815

EP - 828

JO - Nature Genetics

JF - Nature Genetics

IS - 4

M1 - 163

ER -

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

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