Roselli Carolina, Surakka Ida, Olesen Morten S, Sveinbjornsson Gardar, Marston Nicholas A, Choi Seung Hoan, Holm Hilma, Chaffin Mark, Gudbjartsson Daniel, Hill Matthew C, Aegisdottir Hildur, Albert Christine M, Alonso Alvaro, Anderson Christopher D, Arking Dan E, Arnar David O, Barnard John, Benjamin Emelia J, Braunwald Eugene, Brumpton Ben, Campbell Archie, Chami Nathalie, Chasman Daniel I, Cho Kelly, Choi Eue-Keun, Christophersen Ingrid E, Chung Mina K, Conen David, Crijns Harry J, Cutler Michael J, Czuba Tomasz, Damrauer Scott M, Dichgans Martin, Dörr Marcus, Dudink Elton, Duong ThuyVy, Erikstrup Christian, Esko Tõnu, Fatkin Diane, Faul Jessica D, Ferreira Manuel, Freitag Daniel F, Ganesh Santhi K, Gaziano J Michael, Geelhoed Bastiaan, Ghouse Jonas, Gieger Christian, Giulianini Franco, Graham Sarah E, Gudnason Vilmundur, Guo Xiuqing, Haggerty Christopher, Hayward Caroline, Heckbert Susan R, Hveem Kristian, Ito Kaoru, Johnson Renee, Jukema J Wouter, Jurgens Sean J, Kääb Stefan, Kane John P, Kany Shinwan, Kardia Sharon L R, Kavousi Maryam, Khurshid Shaan, Kamanu Frederick K, Kirchhof Paulus, Kleber Marcus E, Knight Stacey, Komuro Issei, Krieger Jose E, Launer Lenore J, Li Dadong, Lin Honghuang, Lin Henry J, Loos Ruth J F, Lotta Luca, Lubitz Steven A, Lunetta Kathryn L, Macfarlane Peter W, Magnusson Patrik K E, Malik Rainer, Mantineo Helene, Marcus Gregory M, März Winfried, McManus David D, Melander Olle, Melloni Giorgio E M, Meyre Pascal B, Miyazawa Kazuo, Mohanty Sanghamitra, Monfort Laia M, Müller-Nurasyid Martina, Nafissi Navid A, Natale Andrea, Nazarian Saman, Ostrowski Sisse R, Pak Hui-Nam, Pang Shichao, Pedersen Ole B, Pedersen Nancy L, Pereira Alexandre C, Pirruccello James P, Preuss Michael, Psaty Bruce M, Pullinger Clive R, Rader Daniel J, Rämö Joel T, Ridker Paul M, Rienstra Michiel, Risch Lorenz, Roden Dan M, Rotter Jerome I, Sabatine Marc S, Schunkert Heribert, Shah Svati H, Shim Jaemin, Shoemaker M Benjamin, Simonson Bridget, Sinner Moritz F, Smit Roelof A J, Smith Jennifer A, Smith Nicholas L, Smith J Gustav, Soliman Elsayed Z, Sørensen Erik, Sotoodehnia Nona, Strbian Daniel, Stricker Bruno H, Teder-Laving Maris, Sun Yan V, Thériault Sébastien, Thorolfsdottir Rosa B, Thorsteinsdottir Unnur, Tveit Arnljot, van der Harst Pim, van Meurs Joyce, Wang Biqi, Weiss Stefan, Wells Quinn S, Weng Lu-Chen, Wilson Peter W, Xiao Ling, Yang Pil-Sung, Yao Jie, Yoneda Zachary T, Zeller Tanja, Zeng Lingyao, Zhao Wei, Zhou Xiang, Zöllner Sebastian, Ruff Christian T, Bundgaard Henning, Willer Cristen, Stefansson Kari, Ellinor Patrick T
Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Nat Genet. 2025 Mar;57(3):539-547. doi: 10.1038/s41588-024-02072-3. Epub 2025 Mar 6.
Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.
心房颤动（AF）是最常见的心律异常，是心力衰竭和中风的主要原因。这项全基因组关联研究的大规模荟萃分析提高了检测单核苷酸变异关联的能力，并发现了350多个与AF相关的遗传位点。我们在139个位点鉴定了与肌肉收缩性、心肌发育和细胞间通讯相关的候选基因。此外，我们在干细胞衍生的心房心肌细胞中使用转座酶可及染色质测序分析法和组蛋白H3赖氨酸4三甲基化分析法检测染色质可及性。我们观察到哨兵变异和心房心肌细胞中优先基因的染色质可及性显著增加。最后，基于我们更新的效应估计值的多基因风险评分（PRS）与CHARGE-AF临床风险评分和先前报道的AF的PRS相比，改善了AF风险预测。已知风险位点的加倍将有助于更深入地了解AF的潜在通路。
