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

Authors

• Seung Hoan Choi
• Sean J. Jurgens
• Ling Xiao
• Matthew C. Hill
• John Blangero, The University of Texas Rio Grande ValleyFollow
• Joanne E. Curran, The University of Texas Rio Grande ValleyFollow
• Ravi Duggirala, The University of Texas Rio Grande Valley
• Harald HH Goring, The University of Texas Rio Grande ValleyFollow
• Michael Mahaney, The University of Texas Rio Grande ValleyFollow
• Juan M. Peralta, The University of Texas Rio Grande ValleyFollow

Document Type

Article

Publication Date

3-2025

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.

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Reprints and permissions

https://rdcu.be/em27m

https://cdr.lib.unc.edu/downloads/q524k329b

Recommended Citation

Choi, S. H., Jurgens, S. J., Xiao, L., Hill, M. C., Haggerty, C. M., Sveinbjörnsson, G., Morrill, V. N., Marston, N. A., Weng, L.-C., Pirruccello, J. P., Arnar, D. O., Gudbjartsson, D. F., Mantineo, H., von Falkenhausen, A. S., Natale, A., Tveit, A., Geelhoed, B., Roselli, C., Van Wagoner, D. R., … Ellinor, P. T. (2025). Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk. Nature Genetics, 57(3), 548–562. https://doi.org/10.1038/s41588-025-02074-9

Publication Title

Nature Genetics

DOI

10.1038/s41588-025-02074-9

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics