Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.
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, Regeneron Genetics Center, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Holm Hilma, Stefansson Kari, Ruff Christian T, Sabatine Marc S, Lunetta Kathryn L, Lubitz Steven A, Ellinor Patrick T
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Аннотация
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.
Для цитирования: 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, Regeneron Genetics Center, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Holm Hilma, Stefansson Kari, Ruff Christian T, Sabatine Marc S, Lunetta Kathryn L, Lubitz Steven A, Ellinor Patrick T. Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.. Nature genetics. 2025. DOI: 10.1038/s41588-025-02074-9.
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