Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk-Reference-Cited by-同舟云学术

Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk

Published:2024-08-01 Issue:8 Volume:9 Page:732
ISSN:2380-6583
Container-title:JAMA Cardiology
language:en
Short-container-title:JAMA Cardiol

Author:

Vad Oliver B.¹²,Monfort Laia M.¹²,Paludan-Müller Christian¹²,Kahnert Konstantin²,Diederichsen Søren Z.¹,Andreasen Laura¹²,Lotta Luca A.³,Nielsen Jonas B.³,Lundby Alicia²,Svendsen Jesper H.¹⁴,Olesen Morten S.¹², ,Baras Aris⁵,Abecasis Gonçalo⁵,Ferrando Adolfo⁵,Cantor Michael⁵,Coppola Giovanni⁵,Deubler Andrew⁵,Economides Aris⁵,Lotta Luca A⁵,Overton John D⁵,Reid Jeffrey G⁵,Shuldiner Alan⁵,Siminovitch Katherine⁵,Portnoy Jason⁵,Jones Marcus B⁵,Mitnaul Lyndon⁵,Fenney Alison⁵,Marchini Jonathan⁵,Ferreira Manuel AR⁵,Ghoussaini Maya⁵,Nafde Mona⁵,Salerno William⁵,Beechert Christina⁵,Brian Erin D⁵,Cremona Laura M⁵,Du Hang⁵,Forsythe Caitlin⁵,Gu Zhenhua⁵,Guevara Kristy⁵,Lattari Michael⁵,Lopez Alexander⁵,Manoochehri Kia⁵,Challa Prathyusha⁵,Pradhan Manasi⁵,Reynoso Raymond⁵,Schiavo Ricardo⁵,Padilla Maria S⁵,Wang Chenggu⁵,Wolf Sarah E⁵,Averitt Amelia⁵,Banerjee Nilanjana⁵,Li Dadong⁵,Malhotra Sameer⁵,Mower Justin⁵,Sarwar Mudasar⁵,Sharma Deepika⁵,Staples Jeffrey C⁵,Yu Sean⁵,Zhang Aaron⁵,Aqeel Muhammad⁵,Mitra George⁵,Gokhale Sujit⁵,Bunyea Andrew⁵,Punuru Krishna P⁵,Sreeram Sanjay⁵,Eom Gisu⁵,Sultan Benjamin⁵,Lanche Rouel⁵,Mahajan Vrushali⁵,Austin Eliot⁵,O'Keeffe Sean⁵,Panea Razvan⁵,Polanco Tommy⁵,Rasool Ayesha⁵,Bai Xiaodong⁵,Zhang Lance⁵,Boutkov Boris⁵,Edelstein Evan⁵,Gorovits Alexander⁵,Guan Ju⁵,Habegger Lukas⁵,Hawes Alicia⁵,Krasheninina Olga⁵,Zarate Samantha⁵,Mansfield Adam J⁵,Maxwell Evan K⁵,Balasubramanian Suganthi⁵,Bao Suying⁵,Sun Kathie⁵,Zhang Chuanyi⁵,Karuppaiya Vikhna Raj Kumar⁵,Backman Joshua⁵,Burch Kathy⁵,Campos Adrian⁵,Chen Lei⁵,Choi Sam⁵,Damask Amy⁵,Ganel Liron⁵,Gaynor Sheila⁵,Geraghty Benjamin⁵,Ghosh Arkopravo⁵,Martinez Salvador R⁵,Gillies Christopher⁵,Gurski Lauren⁵,Herman Joseph⁵,Jorgenson Eric⁵,Joseph Tyler⁵,Kessler Michael⁵,Kosmicki Jack⁵,Lin Nan⁵,Locke Adam⁵,Nakka Priyanka⁵,Landheer Karl⁵,Delaneau Olivier⁵,Marcketta Anthony⁵,Mbatchou Joelle⁵,Moscati Arden⁵,Pandey Aditeya⁵,Pandit Anita⁵,Paulding Charles⁵,Ross Jonathan⁵,Sidore Carlo⁵,Stahl Eli⁵,Suciu Maria⁵,Thornton Timothy⁵,VandeHaar Peter⁵,Vedantam Sailaja⁵,Vrieze Scott⁵,Zhang Jingning⁵,Wang Rujin⁵,Wu Kuan-Han⁵,Ye Bin⁵,Zhang Blair⁵,Ziyatdinov Andrey⁵,Zou Yuxin⁵,Watanabe Kyoko⁵,Tang Mira⁵,Wendt Frank⁵,Hobbs Brian⁵,Silver Jon⁵,Palmer William⁵,Guerreiro Rita⁵,Joshi Amit⁵,Baldassari Antoine⁵,Willer Cristen⁵,Graham Sarah⁵,Mayerhofer Ernst⁵,Haas Mary⁵,Verweij Niek⁵,Hindy George⁵,Bovijn Jonas⁵,De Tanima⁵,Akbari Parsa⁵,Sun Luanluan⁵,Sosina Olukayode⁵,Gilly Arthur⁵,Dornbos Peter⁵,Rodriguez-Flores Juan⁵,Riaz Moeen⁵,Kapoor Manav⁵,Tzoneva Gannie⁵,Jallow Momodou W⁵,Alkelai Anna⁵,Ayer Ariane⁵,Rajagopal Veera⁵,Gelfman Sahar⁵,Kumar Vijay⁵,Otto Jacqueline⁵,Parikshak Neelroop⁵,Guvenek Aysegul⁵,Bras Jose⁵,Alvarez Silvia⁵,Brown Jessie⁵,He Jing⁵,Khiabanian Hossein⁵,Revez Joana⁵,Skead Kimberly⁵,Zavala Valentina⁵,Sul Jae S⁵,Chen Esteban⁵,LeBlanc Michelle G⁵,Mighty Jason⁵,Nishtala Nirupama⁵,Rana Nadia⁵,Rico-Varela Jennifer⁵,Hernandez Jaimee⁵,Schwartz Randi⁵,Hankins Jody⁵,Hart Samuel⁵,Perez-Beals Ann⁵,Solari Gina⁵,Rivera-Picart Johannie⁵,Pagan Michelle⁵,Siceron Sunilbe⁵,Buchanan Adam⁵,Carey David J.⁵,Martin Christa L.⁵,Meyer Michelle⁵,Retterer Kyle⁵,Rolston David⁵

Affiliation:

1. Department of Cardiology, The Heart Centre, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark

2. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

3. Regeneron Genetics Center, Tarrytown, New York

4. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark

5. for the Geisinger MyCode Community Health Initiative and the Regeneron Genetics Center (RGC) Research Team

Abstract

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.

Publisher

American Medical Association (AMA)

Link

https://jamanetwork.com/journals/jamacardiology/articlepdf/2820520/jamacardiology_vad_2024_oi_240031_1722639376.29921.pdf

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