| Title: | Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk |
| Journal: | JAMA Cardiology |
| Published: | 1 Aug 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38922602/ |
| DOI: | https://doi.org/10.1001/jamacardio.2024.1528 |
Publication 11788
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Abstract
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.</p>
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).</p>
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.</p>
Exposures: Rare pLOF variants and an AF PRS.</p>
Main Outcomes and Measures: Risk of AF and incident HF or CM prior to and subsequent to AF diagnosis.</p>
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 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).</p>
Conclusions and Relevance: Rare 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.</p>
16 Keywords
- Adult
- Aged
- Atrial Fibrillation
- Cardiomyopathies
- Case-Control Studies
- Female
- Genetic Predisposition to Disease
- Genetic Variation
- Heart Failure
- Humans
- Incidence
- Loss of Function Mutation
- Male
- Middle Aged
- Risk Factors
- United Kingdom
200 Authors
- Oliver B. Vad
- Laia M. Monfort
- Christian Paludan-Müller
- Konstantin Kahnert
- Søren Z. Diederichsen
- Laura Andreasen
- Luca A. Lotta
- Jonas B. Nielsen
- Alicia Lundby
- Jesper H. Svendsen
- Morten S. Olesen
- Aris Baras
- Gonçalo Abecasis
- Adolfo Ferrando
- Michael Cantor
- Giovanni Coppola
- Andrew Deubler
- Aris Economides
- Luca A Lotta
- John D Overton
- Jeffrey G Reid
- Alan Shuldiner
- Katherine Siminovitch
- Jason Portnoy
- Marcus B Jones
- Lyndon Mitnaul
- Alison Fenney
- Jonathan Marchini
- Manuel AR 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 S Padilla
- Chenggu Wang
- Sarah E Wolf
- Amelia Averitt
- Nilanjana Banerjee
- Dadong Li
- Sameer Malhotra
- Justin Mower
- Mudasar Sarwar
- Deepika Sharma
- Jeffrey C Staples
- Sean Yu
- Aaron Zhang
- Muhammad Aqeel
- George Mitra
- Sujit Gokhale
- Andrew Bunyea
- Krishna P 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
- Adrian Campos
- Lei Chen
- Sam Choi
- Amy Damask
- Liron Ganel
- Sheila Gaynor
- Benjamin Geraghty
- Arkopravo Ghosh
- Salvador R Martinez
- Christopher Gillies
- Lauren Gurski
- Joseph Herman
- Eric Jorgenson
- Tyler Joseph
- Michael Kessler
- Jack Kosmicki
- Nan Lin
- Adam Locke
- Priyanka Nakka
- Karl Landheer
- Olivier Delaneau
- Anthony Marcketta
- Joelle Mbatchou
- Arden Moscati
- Aditeya Pandey
- Anita Pandit
- Charles Paulding
- Jonathan Ross
- Carlo Sidore
- Eli Stahl
- Maria Suciu
- Timothy Thornton
- Peter VandeHaar
- Sailaja Vedantam
- Scott Vrieze
- Jingning Zhang
- Rujin Wang
- Kuan-Han Wu
- Bin Ye
- Blair Zhang
- Andrey Ziyatdinov
- Yuxin Zou
- Kyoko Watanabe
- Mira Tang
- Frank Wendt
- Brian Hobbs
- Jon Silver
- William Palmer
- Rita Guerreiro
- Amit Joshi
- Antoine Baldassari
- Cristen Willer
- Sarah Graham
- Ernst Mayerhofer
- Mary Haas
- Niek Verweij
- George Hindy
- Jonas Bovijn
- Tanima De
- Parsa Akbari
- Luanluan Sun
- Olukayode Sosina
- Arthur Gilly
- Peter Dornbos
- Juan Rodriguez-Flores
- Moeen Riaz
- Manav Kapoor
- Gannie Tzoneva
- Momodou W Jallow
- Anna Alkelai
- Ariane Ayer
- Veera Rajagopal
- Sahar Gelfman
- Vijay Kumar
- Jacqueline Otto
- Neelroop Parikshak
- Aysegul Guvenek
- Jose Bras
- Silvia Alvarez
- Jessie Brown
- Jing He
- Hossein Khiabanian
- Joana Revez
- Kimberly Skead
- Valentina Zavala
- Jae S Sul
- Esteban Chen
- Michelle G LeBlanc
- Jason Mighty
- Nirupama Nishtala
- Nadia Rana
- Jennifer Rico-Varela
- Jaimee Hernandez
- Randi Schwartz
- Jody Hankins
- Samuel Hart
- Ann Perez-Beals
- Gina Solari
- Johannie Rivera-Picart
- Michelle Pagan
- Sunilbe Siceron
- Adam Buchanan
- David J. Carey
- Christa L. Martin
- Michelle Meyer
- Kyle Retterer
- David Rolston
Enabling scientific discoveries that improve human health