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

ImportanceAtrial 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.ObjectiveTo 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 ParticipantsThis 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.ExposuresRare pLOF variants and an AF PRS.Main Outcomes and MeasuresRisk of AF and incident HF or CM prior to and subsequent to AF diagnosis.ResultsA 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 associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. Combined with high PRS, rare pLOF variants conferred an odds ratio of 7.08 (95% CI, 6.03-8.28) for AF. Carriers with high PRS also had a substantial 10-year risk of AF (16% in female individuals and 24% in male individuals older than 60 years). Rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and subsequent to AF (HR, 2.98; 95% CI, 1.89-4.69).Conclusions and RelevanceRare and common genetic variation were associated with an increased risk of AF. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk stratification.