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

Henry, A. ; Engström, G. LU ; Melander, O. LU orcid ; Smith, J.G. LU orcid and Lumbers, R.T. (2025) In Nature Genetics 57(4). p.815-828
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... (More)
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. © The Author(s) 2025. (Less)
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Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Failure, Humans, Male, Polymorphism, Single Nucleotide, Stroke Volume, Ventricular Function, Left, ABC transporter G5, alpha actinin 2, cyclin dependent kinase inhibitor 1A, glucocorticoid receptor, homeobox protein Nkx-2.5, insulin like growth factor binding protein 7, low density lipoprotein, low density lipoprotein receptor, mineralocorticoid receptor, solute carrier organic anion transporter 1B1, transcription factor Pitx2, unclassified drug, African, Article, BAG3 gene, CAMKD2 gene, CAND2 gene, chronic obstructive lung disease, East Asian, European, FLNC gene, forced expiratory volume, forced vital capacity, gene, gene expression, gene frequency, gene locus, genetic association, genetic variability, genome-wide association study, heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, heart infarction, heart left ventricle, heritability, HSPB7 gene, human, KLF12 gene, left ventricular diastolic dysfunction, Mendelian randomization analysis, meta analysis, risk factor, South Asian, STRN gene, systole, classification, etiology, female, genetic predisposition, genetics, heart left ventricle function, heart stroke volume, male, single nucleotide polymorphism
in
Nature Genetics
volume
57
issue
4
pages
14 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:105003400740
  • pmid:40038546
ISSN
1061-4036
DOI
10.1038/s41588-024-02064-3
language
English
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yes
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f0a07189-c0ba-41ca-abe7-c62925b47bb6
date added to LUP
2026-03-11 08:00:34
date last changed
2026-03-12 03:13:15
@article{f0a07189-c0ba-41ca-abe7-c62925b47bb6,
  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. © The Author(s) 2025.}},
  author       = {{Henry, A. and Engström, G. and Melander, O. and Smith, J.G. and Lumbers, R.T.}},
  issn         = {{1061-4036}},
  keywords     = {{Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Heart Failure; Humans; Male; Polymorphism, Single Nucleotide; Stroke Volume; Ventricular Function, Left; ABC transporter G5; alpha actinin 2; cyclin dependent kinase inhibitor 1A; glucocorticoid receptor; homeobox protein Nkx-2.5; insulin like growth factor binding protein 7; low density lipoprotein; low density lipoprotein receptor; mineralocorticoid receptor; solute carrier organic anion transporter 1B1; transcription factor Pitx2; unclassified drug; African; Article; BAG3 gene; CAMKD2 gene; CAND2 gene; chronic obstructive lung disease; East Asian; European; FLNC gene; forced expiratory volume; forced vital capacity; gene; gene expression; gene frequency; gene locus; genetic association; genetic variability; genome-wide association study; heart failure; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; heart infarction; heart left ventricle; heritability; HSPB7 gene; human; KLF12 gene; left ventricular diastolic dysfunction; Mendelian randomization analysis; meta analysis; risk factor; South Asian; STRN gene; systole; classification; etiology; female; genetic predisposition; genetics; heart left ventricle function; heart stroke volume; male; single nucleotide polymorphism}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{815--828}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes}},
  url          = {{http://dx.doi.org/10.1038/s41588-024-02064-3}},
  doi          = {{10.1038/s41588-024-02064-3}},
  volume       = {{57}},
  year         = {{2025}},
}