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Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.
Tuesday,2025-04-08 15:13 America/Los_Angeles — ecterry
| Title | Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk. |
| Publication Type | Journal Article |
| Year of Publication | 2025 |
| Authors | Choi, SHoan, Jurgens, SJ, Xiao, L, Hill, MC, Haggerty, CM, Sveinbjörnsson, G, Morrill, VN, Marston, NA, Weng, L-C, Pirruccello, JP, Arnar, DO, Gudbjartsson, DFannar, 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, LCoulter, 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, J Smith, G, Roberts, JD, Raffield, LM, M Shoemaker, B, Cho, MH, Cutler, MJ, Rienstra, M, Chung, MK, Olesen, MS, Sinner, MF, Sotoodehnia, N, Kirchhof, P, Loos, RJF, Nazarian, S, Mohanty, S, Damrauer, SM, Kääb, S, Heckbert, SR, Redline, S, Shah, SH, Tanaka, T, Ebana, Y, Holm, H, Stefansson, K, Ruff, CT, Sabatine, MS, Lunetta, KL, Lubitz, SA, Ellinor, PT |
| Corporate/Institutional Authors | Regeneron Genetics Center, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium |
| Journal | Nat Genet |
| Volume | 57 |
| Issue | 3 |
| Pagination | 548-562 |
| Date Published | 2025 Mar |
| ISSN | 1546-1718 |
| Keywords | Atrial Fibrillation, Case-Control Studies, Exome Sequencing, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Myocytes, Cardiac, Risk Factors |
| Abstract | <p>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.</p> |
| DOI | 10.1038/s41588-025-02074-9 |
| Alternate Journal | Nat Genet |
| PubMed ID | 40050430 |
| PubMed Central ID | 7577553 |
| Grant List | K24HL105780 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / U01 AG068221 / AG / NIA NIH HHS / United States K08HL153950 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 75N92019D00031 / HL / NHLBI NIH HHS / United States 18SFRN34110082 / / American Heart Association (American Heart Association, Inc.) / R01HL141989 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 648131 / / EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) / 847770 / / EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) / 18SFRN34230127 / / American Heart Association (American Heart Association, Inc.) / R01HL157635 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 1U01AG068221-01A1 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / R01HL147148 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / R01HL111314 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / R01HL155197 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 9SFRN34830063 / / American Heart Association (American Heart Association, Inc.) / 1U01AG058589-01A1 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 2019-0526 / / Hjärt-Lungfonden (Swedish Heart-Lung Foundation) / R01HL092577 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / R35HL135818 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 18SFRN34250007 / / American Heart Association (American Heart Association, Inc.) / IRC15-0067 / / Stiftelsen för Strategisk Forskning (Swedish Foundation for Strategic Research) / R01HL137927 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 32473B_176178 / / Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) / AA/18/2/34218 / / British Heart Foundation (BHF) / 1R01HL164824-01 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / HL113338 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / R01HL111024 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / R01HL141901 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / PG/20/22/35093 / / British Heart Foundation (BHF) / HL116690 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 961045 / / American Heart Association (American Heart Association, Inc.) / 18SFRN34110067 / / American Heart Association (American Heart Association, Inc.) / P01HL158505 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / R01HL089856 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / IK2-CX001780 / / U.S. Department of Veterans Affairs (Department of Veterans Affairs) / 349-2006-237 / / Vetenskapsrådet (Swedish Research Council) / K08HL159346 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 17K07251 / / MEXT | Japan Society for the Promotion of Science (JSPS) / 2009-1039 / / Vetenskapsrådet (Swedish Research Council) / 32003B_197524 / / Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) / 03-007-2022-0035 / / Hartstichting (Dutch Heart Foundation) / 33CS30_177520 / / Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) / JP18H02804 / / MEXT | Japan Society for the Promotion of Science (JSPS) / 2019-0354 / / Svenska Sällskapet för Medicinsk Forskning (Swedish Society for Medical Research) / 19SFRN34830063 / / American Heart Association (American Heart Association, Inc.) / 2021-02273 / / Vetenskapsrådet (Swedish Research Council) / 18SFRN34110067. / / American Heart Association (American Heart Association, Inc.) / PG/17/30/32961 / / British Heart Foundation (BHF) / 33CS30_148474 / / Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) / R01HL149352 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 1R01HL139731 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 2R01HL127564-05A1 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 20CDA35260081 / / American Heart Association (American Heart Association, Inc.) / HL-093613 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / 1R01HL128914 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / HL43680 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) / Ki 731/4-1 / / Deutsche Forschungsgemeinschaft (German Research Foundation) / |
ePub date:
25/03