TY - JOUR
T1 - Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk
AU - Regeneron Genetics Center
AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
AU - Choi, Seung Hoan
AU - Jurgens, Sean J.
AU - Xiao, Ling
AU - Hill, Matthew C.
AU - Haggerty, Christopher M.
AU - Sveinbjörnsson, Garðar
AU - Morrill, Valerie N.
AU - Marston, Nicholas A.
AU - Weng, Lu Chen
AU - Pirruccello, James P.
AU - Arnar, David O.
AU - Gudbjartsson, Daniel Fannar
AU - Mantineo, Helene
AU - von Falkenhausen, Aenne S.
AU - Natale, Andrea
AU - Tveit, Arnljot
AU - Geelhoed, Bastiaan
AU - Roselli, Carolina
AU - Van Wagoner, David R.
AU - Darbar, Dawood
AU - Haase, Doreen
AU - Soliman, Elsayed Z.
AU - Davogustto, Giovanni E.
AU - Jun, Goo
AU - Calkins, Hugh
AU - Anderson, Jeffrey L.
AU - Brody, Jennifer A.
AU - Halford, Jennifer L.
AU - Barnard, John
AU - Hokanson, John E.
AU - Smith, Jonathan D.
AU - Bis, Joshua C.
AU - Young, Kendra
AU - Johnson, Linda S.B.
AU - Risch, Lorenz
AU - Gula, Lorne J.
AU - Kwee, Lydia Coulter
AU - Chaffin, Mark D.
AU - Kühne, Michael
AU - Preuss, Michael
AU - Gupta, Namrata
AU - Nafissi, Navid A.
AU - Smith, Nicholas L.
AU - Nilsson, Peter M.
AU - van der Harst, Pim
AU - Wells, Quinn S.
AU - Judy, Renae L.
AU - Schnabel, Renate B.
AU - Johnson, Renee
AU - Ochs-Balcom, Heather
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
PY - 2025/3
Y1 - 2025/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105001065870
U2 - 10.1038/s41588-025-02074-9
DO - 10.1038/s41588-025-02074-9
M3 - Article
C2 - 40050430
AN - SCOPUS:105001065870
SN - 1061-4036
VL - 57
SP - 548
EP - 562
JO - Nature Genetics
JF - Nature Genetics
IS - 3
M1 - e020163
ER -