Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk

作者：Oliver Bundgaard Vad, Laia M. Monfort, Christian Paludan‐Müller, Konstantin Kahnert, Søren Zöga Diederichsen, Laura Andreasen, Luca A. Lotta, Jonas B. Nielsen, Alicia Lundby, Jesper Hastrup Svendsen, Morten Olesen, Aris Baras, Gonçalo R. Abecasis, Adolfo A. Ferrando, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris N. Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Katherine Siminovitch, Jason Portnoy, Marcus B. Jones, Lyndon J. Mitnaul, Alison Fenney, Jonathan Marchini, Manuel A. R. Ferreira, Maya Ghoussaini, Mona Nafde, William Salerno, Christina Beechert, Erin D. Brian, Laura M. Cremona, Hang Du, Caitlin Forsythe, Zhenhua Gu, Kristy Guevara, Michael Lattari, Alexander Lopez, Kia Manoochehri, Prathyusha Challa, Manasi Pradhan, Raymond Reynoso, Ricardo Schiavo, Maria Sotiropoulos Padilla, Chenggu Wang, Sarah E. Wolf, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Justin Mower, Mudasar Sarwar, Deepika Sharma, Jeffrey Staples, Sean Yu, Aaron Zhang, Muhammad Aqeel, George Mitra, Sujit Gokhale, Andrew Bunyea, Krishna Pawan Punuru, Sanjay Sreeram, Gisu Eom, Benjamin Sultan, Rouel Lanche, Vrushali Mahajan, Eliot Austin, Sean O’Keeffe, Razvan Panea, Tommy Polanco, Ayesha Rasool, Xiaodong Bai, Lance Zhang, Boris Boutkov, Evan Edelstein, Alexander Gorovits, Ju Guan, Lukas Habegger, Alicia Hawes, Olga Krasheninina, Samantha Zarate, Adam J. Mansfield, Evan K. Maxwell, Suganthi Balasubramanian, Suying Bao, Kathie Sun, Chuanyi Zhang, Vikhna Raj Kumar Karuppaiya, Joshua Backman, Kathy Burch, Adrián I. Campos, Lei Chen, Sam Choi, Amy Damask, Liron Ganel, Sheila M. Gaynor, Benjamin Geraghty, Arkopravo Ghosh, Salvador Romero Martinez, Christopher E. Gillies, Lauren Gurski, Joseph Herman, Eric Jorgenson, Tyler Joseph, Michael D. Kessler, Jack A. Kosmicki, Nan Lin, Adam E. Locke, Priyanka Nakka, Karl Landheer, Olivier Delaneau, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Aditeya Pandey, Anita Pandit, Charles Paulding, Jonathan Ross, Carlo Sidore, Eli A. Stahl, Maria Suciu, Timothy A. Thornton, Peter VandeHaar, Sailaja Vedantam, Scott Vrieze, Jingning Zhang, Rujin Wang, Kuan-Han H. Wu, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Yuxin Zou, Kyoko Watanabe, Mira Tang, Frank R. Wendt, Brian P. Hobbs, Jon Silver, William Palmer, Rita Guerreiro, Amit D. Joshi, Antoine Baldassari, Cristen J. Willer, Sarah E. Graham, Ernst Mayerhofer, Mary E. Haas, Niek Verweij, George Hindy, Jonas Bovijn, Tanima De, Parsa Akbari, Luanluan Sun, Olukayode Sosina, Arthur Gilly, Peter Dornbos, Juan L. Rodríguez-Flores, Moeen Riaz, Manav Kapoor, Gannie Tzoneva, Momodou W. Jallow, Anna Alkelai, Ariane Ayer, Veera M. Rajagopal, Sahar Gelfman, Vijay Kumar, Jacqueline M. Otto, Neelroop Parikshak, Ayşegül Güvenek, José Brás, Silvia Álvarez, Jessie Brown, Jing He, Hossein Khiabanian, Joana Revez, Kimberly Skead, Valentina A. Zavala, Jae Soon Sul, Esteban Chen, Michelle G. LeBlanc, Jason Mighty, Nirupama Nishtala, Nadia A. Rana, Jennifer Rico‐Varela, Jaimee Hernandez, Randi Schwartz, Jody Hankins, Samuel F. M. Hart, Ann Perez-Beals, Gina Solari, Johannie Rivera-Picart, Michelle Pagan, Sunilbe Siceron, Adam H. Buchanan, David J. Carey, Christa Lese Martin, Michelle N. Meyer, Kyle Retterer, David D.K. Rolston · 发表于：JAMA Cardiology · 年份：2024 · DOI：10.1001/jamacardio.2024.1528 · 被引用次数：51 · 研究领域：Genetic Associations and Epidemiology、Genomics and Rare Diseases、Atrial Fibrillation Management and Outcomes

Importance: Atrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts. Objective: To identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS). Design, Setting, and Participants: This was a genetic association and nested case-control study. The impact of rare pLOF variants was evaluated on the risk of incident AF. HF and CM were assessed in cause-specific Cox regressions. End of follow-up was July 1, 2022. Data were analyzed from January to October 2023. The UK Biobank enrolled 502 480 individuals aged 40 to 69 years at inclusion in the United Kingdom between March 13, 2006, and October 1, 2010. UK residents of European ancestry were included. Individuals with prior diagnosis of AF were excluded from analyses of incident AF. Exposures: Rare pLOF variants and an AF PRS. Main Outcomes and Measures: Risk of AF and incident HF or CM prior to and subsequent to AF diagnosis. Results: A total of 403 990 individuals (218 489 [54.1%] female) with a median (IQR) age of 58 (51-63) years were included; 24 447 were diagnosed with incident AF over a median (IQR) follow-up period of 13.3 (12.4-14.0) years. Rare pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were ...