Contributions of Common, Rare, and Somatic Genetic Variants to Incidence of Atrial Fibrillation

Rufan Zhang^{1

2}, Min Seo Kim^{3

4}, Wanqing Yin^{1

2

5}, Shuangqiao Liao^{1

2

5}, Xinyu Zhu^{1

2

6}, Xiong Yang^{1

2}, Kang Yu^{1

2

5}, Yang Sui^{3

4}, Carolina Roselli⁴, Shaan Khurshid^{3

4

7}, Qiuli Chen^{1

2

5}, Yunga A^{1

2

5}, Hongqiang Zhao^{1

2}, Tingfeng Xu^{1

2

5}, Xiufeng Huang⁸, Jun Pu⁹, Zhaoqi Liu^{1

2

5

6}, Pradeep Natarajan^{3

4

10

11}, Guangyao Zhai¹², Patrick T Ellinor^{3

4

7

11

13}, Minxian Wang^{1

2

5

6

14

15

16}, Akl C Fahed^{3

4

13}

Affiliations

¹ China National Center for Bioinformation, Beijing, China.
² Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
³ Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston.
⁵ University of Chinese Academy of Sciences, Beijing, China.
⁶ College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
⁷ Demoulas Family Foundation Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston.
⁸ Zhejiang Provincial Clinical Research Center for Pediatric Precision Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
⁹ Department of Cardiology, Renji Hospital, School of Medicine, State Key Laboratory for Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China.
¹⁰ Center for Genomic Medicine, Massachusetts General Hospital, Boston.
¹¹ Harvard Medical School, Boston, Massachusetts.
¹² Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, China.
¹³ Division of Cardiology, Massachusetts General Hospital, Boston.
¹⁴ Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
¹⁵ Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, China.
¹⁶ Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, China.

PMID: 41060636
PMCID: PMC12509083 (available on 2026-10-08)
DOI: 10.1001/jamacardio.2025.3664

Contributions of Common, Rare, and Somatic Genetic Variants to Incidence of Atrial Fibrillation

Rufan Zhang et al. JAMA Cardiol. 2025.

. 2025 Oct 8:e253664.

doi: 10.1001/jamacardio.2025.3664. Online ahead of print.

Authors

Affiliations

¹ China National Center for Bioinformation, Beijing, China.
² Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
³ Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston.
⁵ University of Chinese Academy of Sciences, Beijing, China.
⁶ College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
⁷ Demoulas Family Foundation Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston.
⁸ Zhejiang Provincial Clinical Research Center for Pediatric Precision Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
⁹ Department of Cardiology, Renji Hospital, School of Medicine, State Key Laboratory for Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China.
¹⁰ Center for Genomic Medicine, Massachusetts General Hospital, Boston.
¹¹ Harvard Medical School, Boston, Massachusetts.
¹² Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, China.
¹³ Division of Cardiology, Massachusetts General Hospital, Boston.
¹⁴ Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
¹⁵ Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, China.
¹⁶ Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, China.

PMID: 41060636
PMCID: PMC12509083 (available on 2026-10-08)
DOI: 10.1001/jamacardio.2025.3664

Abstract

Importance: Atrial fibrillation (AF) has a complex genetic architecture involving common, rare, and somatic variants. The association between these components requires further investigation.

Objective: To examine the individual and combined contributions of polygenic, monogenic, and somatic genetic variants to AF incidence, and develop an integrated genomic model (IGM-AF) for improved risk prediction.

Design, setting, and participants: This cohort study used whole-genome sequence data from participants of the UK Biobank, with follow-up for AF events through hospital records, death registries, and self-report. The UK Biobank recruited participants aged 40 to 69 years in the UK between 2006 and 2010. Study data were analyzed from August 2022 to November 2024.

Exposures: IGM-AF comprising an AF polygenic risk score (PRS), a composite rare variant gene set (AFgeneset), and somatic variants associated with clonal hematopoiesis of indeterminate potential (CHIP). Clinical AF risk was estimated using the Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) score.

Main outcomes and measures: The primary outcome was hazard ratios (HRs) for 5-year incident AF attributable to PRS, AFgeneset, CHIP, and their interactions. The predictive performance of IGM-AF and its components was quantified using HRs, C statistics, and reclassification indices.

Results: A total of 416 085 individuals (mean [SD] age, 56.6 [8.0] years; 224 642 female [54.0%]) with 30 797 AF cases were included. The PRS (HR per 1 SD, 1.65; 95% CI, 1.63-1.67; P < 1 × 10-8), AFgeneset (HR, 1.63; 95% CI, 1.52-1.75; P = 1.46 × 10-42), and CHIP (HR, 1.26; 95% CI, 1.15-1.38; P = 1.41 × 10-6) were associated with incident AF. The 5-year cumulative incidence of AF was at least 2-fold among individuals having all 3 genetic drivers (common, rare, and somatic drivers) compared with those with only 1 driver. Integration of IGM-AF with a clinical risk model (CHARGE-AF) showed higher predictive performance (C statistic, 0.80; 95% CI, 0.80-0.80) compared with IGM-AF and CHARGE-AF alone. The classification of the at-risk population for AF was improved when IGM-AF was added to CHARGE-AF (net reclassification index, 0.08; 95% CI, 0.07-0.09).

Conclusions and relevance: Results of this cohort study demonstrated the complementary value of common, rare, and somatic variants in shaping genomic AF risk. Leveraging comprehensive genetic information may enhance screening and preventive interventions for AF.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Sui reported receiving support from a TOPMed Fellowship from the National Heart, Lung, and Blood Institute and being a consultant for Arboretum LifeSciences Inc. Dr Roselli reported receiving grants from Bayer AG to the Broad Institute focused on the development of therapeutics for cardiovascular disease and personal fees as a full-time employee from GSK as of July 1, 2024, outside the submitted work. Dr Natarajan reported receiving grants from Allelica, Amgen, Apple, Boston Scientific, Cleerly, Genentech/Roche, Ionis, Novartis, Silence Therapeutics; personal fees from AIRNA, Allelica, Apple, AstraZeneca, Bain Capital, Blackstone Life Sciences, Bristol Myers Squibb, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, Novo Nordisk, TenSixteen Bio, Tourmaline Bio; equity from Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, TenSixteen Bio; and royalties from Recora for intensive cardiac rehabilitation outside the submitted work. Dr Ellinor reported receiving grants from Bayer, Novo Nordisk, BMS, Pfizer; advisory board/consultation fees from Bayer; and sponsored research support from Bayer AG, IBM Research, Bristol Myers Squibb, Pfizer, and Novo Nordisk during the conduct of the study. Dr Fahed reported being cofounder of Goodpath and Avigena and serving as scientific advisor to MyOme, Arboretum Health, HeartFlow, and Aditum Bio outside the submitted work. No other disclosures were reported.

References

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Contributions of Common, Rare, and Somatic Genetic Variants to Incidence of Atrial Fibrillation

Affiliations

Contributions of Common, Rare, and Somatic Genetic Variants to Incidence of Atrial Fibrillation

Authors

Affiliations

Abstract

Conflict of interest statement

References

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