Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.
Journal
Nature genetics
Journal Volume
57
Journal Issue
3
Start Page
548
End Page
562
ISSN
1546-1718
Date Issued
2025-03
Author(s)
Choi, Seung Hoan
Jurgens, Sean J
Xiao, Ling
Hill, Matthew C
Haggerty, Christopher M
Sveinbjörnsson, Garðar
Morrill, Valerie N
Marston, Nicholas A
Weng, Lu-Chen
Pirruccello, James P
Arnar, David O
Gudbjartsson, Daniel Fannar
Mantineo, Helene
von Falkenhausen, Aenne S
Natale, Andrea
Tveit, Arnljot
Geelhoed, Bastiaan
Roselli, Carolina
Van Wagoner, David R
Darbar, Dawood
Haase, Doreen
Soliman, Elsayed Z
Davogustto, Giovanni E
Jun, Goo
Calkins, Hugh
Anderson, Jeffrey L
Brody, Jennifer A
Halford, Jennifer L
Barnard, John
Hokanson, John E
Smith, Jonathan D
Bis, Joshua C
Young, Kendra
Johnson, Linda S B
Risch, Lorenz
Gula, Lorne J
Kwee, Lydia Coulter
Chaffin, Mark D
Kühne, Michael
Preuss, Michael
Gupta, Namrata
Nafissi, Navid A
Smith, Nicholas L
Nilsson, Peter M
van der Harst, Pim
Wells, Quinn S
Judy, Renae L
Schnabel, Renate B
Johnson, Renee
Smit, Roelof A J
Gabriel, Stacey
Knight, Stacey
Furukawa, Tetsushi
Blackwell, Thomas W
Nauffal, Victor
Wang, Xin
Min, Yuan-I
Yoneda, Zachary T
Laksman, Zachary W M
Bezzina, Connie R
Alonso, Alvaro
Psaty, Bruce M
Albert, Christine M
Arking, Dan E
Roden, Dan M
Chasman, Daniel I
Rader, Daniel J
Conen, David
McManus, David D
Fatkin, Diane
Benjamin, Emelia J
Boerwinkle, Eric
Marcus, Gregory M
Christophersen, Ingrid E
Smith, J Gustav
Roberts, Jason D
Raffield, Laura M
Shoemaker, M Benjamin
Cho, Michael H
Cutler, Michael J
Rienstra, Michiel
Chung, Mina K
S Olesen, Morten
Sinner, Moritz F
Sotoodehnia, Nona
Kirchhof, Paulus
Loos, Ruth J F
Nazarian, Saman
Mohanty, Sanghamitra
Damrauer, Scott M
Kaab, Stefan
Heckbert, Susan R
Redline, Susan
Shah, Svati H
Tanaka, Toshihiro
Ebana, Yusuke
Holm, Hilma
Stefansson, Kari
Ruff, Christian T
Sabatine, Marc S
Lunetta, Kathryn L
Lubitz, Steven A
Ellinor, Patrick T
et al.
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.
Type
journal article