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

Publication ,  Journal Article
Choi, SH; Jurgens, SJ; Xiao, L; Hill, MC; Haggerty, CM; Sveinbjörnsson, G; Morrill, VN; Marston, NA; Weng, L-C; Pirruccello, JP; Arnar, DO ...
Published in: Nat Genet
March 2025
Published version (DOI) Link to item

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.

Duke Scholars

Svati Hasmukh Shah
Author Svati Hasmukh Shah Medicine, Cardiology
Allison Elizabeth Ashley-Koch
Author Allison Elizabeth Ashley-Koch Medicine, Nephrology

Published In

Nat Genet

DOI

10.1038/s41588-025-02074-9

EISSN

1546-1718

Publication Date

March 2025

Volume

57

Issue

3

Start / End Page

548 / 562

Location

United States

Related Subject Headings

  • Myocytes, Cardiac
  • Humans
  • Genome-Wide Association Study
  • Genetic Variation
  • Genetic Predisposition to Disease
  • Exome Sequencing
  • Developmental Biology
  • Case-Control Studies
  • Atrial Fibrillation
  • 3105 Genetics
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Choi, S. H., Jurgens, S. J., Xiao, L., Hill, M. C., Haggerty, C. M., Sveinbjörnsson, G., … Ellinor, P. T. (2025). Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk. Nat Genet, 57(3), 548–562. https://doi.org/10.1038/s41588-025-02074-9
Choi, Seung Hoan, Sean J. Jurgens, Ling Xiao, Matthew C. Hill, Christopher M. Haggerty, Garðar Sveinbjörnsson, Valerie N. Morrill, et al. “Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.” Nat Genet 57, no. 3 (March 2025): 548–62. https://doi.org/10.1038/s41588-025-02074-9.
Choi SH, Jurgens SJ, Xiao L, Hill MC, Haggerty CM, Sveinbjörnsson G, et al. Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk. Nat Genet. 2025 Mar;57(3):548–62.
Choi, Seung Hoan, et al. “Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.” Nat Genet, vol. 57, no. 3, Mar. 2025, pp. 548–62. Pubmed, doi:10.1038/s41588-025-02074-9.
Choi SH, Jurgens SJ, Xiao L, Hill MC, Haggerty CM, Sveinbjörnsson G, Morrill VN, Marston NA, Weng L-C, Pirruccello JP, Arnar DO, Gudbjartsson DF, Mantineo H, von Falkenhausen AS, Natale A, Tveit A, Geelhoed B, Roselli C, Van Wagoner DR, Darbar D, Haase D, Soliman EZ, Davogustto GE, Jun G, Calkins H, Anderson JL, Brody JA, Halford JL, Barnard J, Hokanson JE, Smith JD, Bis JC, Young K, Johnson LSB, Risch L, Gula LJ, Kwee LC, Chaffin MD, Kühne M, Preuss M, Gupta N, Nafissi NA, Smith NL, Nilsson PM, van der Harst P, Wells QS, Judy RL, Schnabel RB, Johnson R, Smit RAJ, Gabriel S, Knight S, Furukawa T, Blackwell TW, Nauffal V, Wang X, Min Y-I, Yoneda ZT, Laksman ZWM, Bezzina CR, Alonso A, Psaty BM, Albert CM, Arking DE, Roden DM, Chasman DI, Rader DJ, Conen D, McManus DD, Fatkin D, Benjamin EJ, Boerwinkle E, Marcus GM, Christophersen IE, Smith JG, Roberts JD, Raffield LM, Shoemaker MB, Cho MH, Cutler MJ, Rienstra M, Chung MK, S Olesen M, Sinner MF, Sotoodehnia N, Kirchhof P, Loos RJF, Nazarian S, Mohanty S, Damrauer SM, Kaab S, Heckbert SR, Redline S, Shah SH, Tanaka T, Ebana Y, Regeneron Genetics Center, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Holm H, Stefansson K, Ruff CT, Sabatine MS, Lunetta KL, Lubitz SA, Ellinor PT. Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk. Nat Genet. 2025 Mar;57(3):548–562.

Published In

Nat Genet

DOI

10.1038/s41588-025-02074-9

EISSN

1546-1718

Publication Date

March 2025

Volume

57

Issue

3

Start / End Page

548 / 562

Location

United States

Related Subject Headings

  • Myocytes, Cardiac
  • Humans
  • Genome-Wide Association Study
  • Genetic Variation
  • Genetic Predisposition to Disease
  • Exome Sequencing
  • Developmental Biology
  • Case-Control Studies
  • Atrial Fibrillation
  • 3105 Genetics