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Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk

Choi, S.H. ; Johnson, L.S.B. LU ; Nilsson, P.M. LU ; Smith, J.G. LU orcid and Ellinor, P.T. (2025) In Nature Genetics 57(3). p.548-562
Abstract
Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration... (More)
Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025. (Less)
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Atrial Fibrillation, Case-Control Studies, Exome Sequencing, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Myocytes, Cardiac, Risk Factors, transcription factor GATA 4, action potential duration, adult, Article, atrial fibrillation, cardiac muscle cell, cardiovascular risk, case control study, clustered regularly interspaced short palindromic repeat, cohort analysis, controlled study, ctnna3 gene, disease association, fam189a2 gene, female, gene, gene deletion, gene duplication, gene knockout, genetic association, genetic variation, heart atrium, homeostasis, human, kdm5b gene, lmna gene, major clinical study, male, middle aged, mybpc3 gene, pkp2 gene, protein depletion, stem cell, transcriptomics, UK Biobank, whole genome sequencing, genetic predisposition, genetics, genome-wide association study, meta analysis, metabolism, pathology, risk factor, whole exome sequencing
in
Nature Genetics
volume
57
issue
3
pages
15 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:105001065870
  • pmid:40050430
ISSN
1061-4036
DOI
10.1038/s41588-025-02074-9
language
English
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yes
id
4105e1f4-2b30-42b7-9b67-86d5e64594f6
date added to LUP
2026-03-06 11:37:34
date last changed
2026-03-09 10:20:04
@article{4105e1f4-2b30-42b7-9b67-86d5e64594f6,
  abstract     = {{Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.}},
  author       = {{Choi, S.H. and Johnson, L.S.B. and Nilsson, P.M. and Smith, J.G. and Ellinor, P.T.}},
  issn         = {{1061-4036}},
  keywords     = {{Atrial Fibrillation; Case-Control Studies; Exome Sequencing; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Myocytes, Cardiac; Risk Factors; transcription factor GATA 4; action potential duration; adult; Article; atrial fibrillation; cardiac muscle cell; cardiovascular risk; case control study; clustered regularly interspaced short palindromic repeat; cohort analysis; controlled study; ctnna3 gene; disease association; fam189a2 gene; female; gene; gene deletion; gene duplication; gene knockout; genetic association; genetic variation; heart atrium; homeostasis; human; kdm5b gene; lmna gene; major clinical study; male; middle aged; mybpc3 gene; pkp2 gene; protein depletion; stem cell; transcriptomics; UK Biobank; whole genome sequencing; genetic predisposition; genetics; genome-wide association study; meta analysis; metabolism; pathology; risk factor; whole exome sequencing}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{548--562}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk}},
  url          = {{http://dx.doi.org/10.1038/s41588-025-02074-9}},
  doi          = {{10.1038/s41588-025-02074-9}},
  volume       = {{57}},
  year         = {{2025}},
}