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Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases

Roselli, C. ; Czuba, T. LU ; Melander, O. LU orcid ; Smith, J.G. LU orcid and Ellinor, P.T. (2025) In Nature Genetics 57(3). p.539-547
Abstract
Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell–cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial... (More)
Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell–cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025. (Less)
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keywords
Atrial Fibrillation, Chromatin, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Risk Factors, histone H3, lysine, Article, atrial fibrillation, cardiac muscle, cell communication, chromatin, gene locus, genetic risk score, genome-wide association study, human, meta analysis, muscle contractility, muscle development, single nucleotide polymorphism, cardiac muscle cell, female, genetic predisposition, genetics, male, metabolism, multifactorial inheritance, pathology, risk factor
in
Nature Genetics
volume
57
issue
3
pages
9 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:105001208957
  • pmid:40050429
ISSN
1061-4036
DOI
10.1038/s41588-024-02072-3
language
English
LU publication?
yes
id
110af33e-2051-45f6-9774-e06b573527f5
date added to LUP
2026-03-05 14:09:11
date last changed
2026-03-09 10:20:49
@article{110af33e-2051-45f6-9774-e06b573527f5,
  abstract     = {{Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell–cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.}},
  author       = {{Roselli, C. and Czuba, T. and Melander, O. and Smith, J.G. and Ellinor, P.T.}},
  issn         = {{1061-4036}},
  keywords     = {{Atrial Fibrillation; Chromatin; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Multifactorial Inheritance; Myocytes, Cardiac; Polymorphism, Single Nucleotide; Risk Factors; histone H3; lysine; Article; atrial fibrillation; cardiac muscle; cell communication; chromatin; gene locus; genetic risk score; genome-wide association study; human; meta analysis; muscle contractility; muscle development; single nucleotide polymorphism; cardiac muscle cell; female; genetic predisposition; genetics; male; metabolism; multifactorial inheritance; pathology; risk factor}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{539--547}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases}},
  url          = {{http://dx.doi.org/10.1038/s41588-024-02072-3}},
  doi          = {{10.1038/s41588-024-02072-3}},
  volume       = {{57}},
  year         = {{2025}},
}