Cardiomyopathy Gene Variants and Polygenic Risk Scores in Atrial Fibrillation: Evidence for an Atrial-First Phenotype

Guilherme L da Rocha¹, James Feiner², Julieta Lazarte³, Keona Pang⁴, Yanran Li⁵, Ann Le⁴, Alice Man², Nazia Pathan⁶, Richard P Whitlock¹, Emilie P Belley-Côté⁷, David Conen⁸, Jorge A Wong⁷, William F McIntyre⁷, Jeff S Healey⁷, Connie R Bezzina⁹, Hugh Watkins¹⁰, James S Ware¹¹, Rafik Tadros¹², Guillaume Paré¹, Jason D Roberts¹³

Affiliations

¹ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
² Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
³ Department of Medicine, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
⁴ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada.
⁵ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁶ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁷ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Division of Cardiology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁸ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Department of Medicine, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
⁹ Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Center, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
¹⁰ Oxford Biomedical Research Centre and Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
¹¹ National Heart and Lung Institute and MRC Laboratory of Medical Sciences, Imperial College London, London, United Kingdom.
¹² Cardiovascular Genetics Centre, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
¹³ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Division of Cardiology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: jason.roberts@phri.ca.

PMID: 41706057
DOI: 10.1016/j.jacc.2025.12.014

Cardiomyopathy Gene Variants and Polygenic Risk Scores in Atrial Fibrillation: Evidence for an Atrial-First Phenotype

Guilherme L da Rocha et al. J Am Coll Cardiol. 2026.

. 2026 Feb 9:S0735-1097(25)10428-2.

doi: 10.1016/j.jacc.2025.12.014. Online ahead of print.

Authors

Affiliations

¹ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
² Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
³ Department of Medicine, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
⁴ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada.
⁵ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁶ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁷ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Division of Cardiology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁸ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Department of Medicine, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
⁹ Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Center, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
¹⁰ Oxford Biomedical Research Centre and Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
¹¹ National Heart and Lung Institute and MRC Laboratory of Medical Sciences, Imperial College London, London, United Kingdom.
¹² Cardiovascular Genetics Centre, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
¹³ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada; Division of Cardiology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: jason.roberts@phri.ca.

PMID: 41706057
DOI: 10.1016/j.jacc.2025.12.014

Abstract

Background: Atrial fibrillation (AF) is heritable and its complex underlying genetic substrate is gradually being unraveled.

Objectives: We sought to explore the impact of disease-causing cardiomyopathy variants on the risk of AF after adjustment for incident ventricular cardiomyopathy and clinical heart failure in 2 cohort studies (UK Biobank [UKB] and All of Us [AoU]) and evaluate the utility of polygenic risk scores (PRS) to further discern the risk of atrial and ventricular phenotypes in carriers.

Methods: Cox regression was used to evaluate for associations between disease-causing variants within genes for 3 cardiomyopathies (dilated cardiomyopathy [DCM], hypertrophic cardiomyopathy [HCM], and arrhythmogenic right ventricular cardiomyopathy) and AF. Disease-specific PRSs for AF, DCM, and HCM stratified study participants into quintiles. A HR random-effects meta-analysis was performed using the DerSimonian-Laird method. The Kaplan-Meier method was used to ascertain cumulative incidence from birth to 75 years of age.

Results: Among 655,796 individuals from UKB and AoU, presence of a disease-causing variant was associated with an increased AF hazard (HR: 1.73; 95% CI: 1.59-1.89; P < 0.001), including after adjustment for incident ventricular cardiomyopathy or clinical heart failure (adjusted to HR: 1.55; 95% CI: 1.46-1.64, P < 0.001). The cumulative AF risk for study participants with a putative disease-causing rare variant and a PRS_AF within the top-risk quintile ranged from 32.5% (UKB) to 32.4% (AoU) relative to 9.8% (UKB) and 11.0% (AoU) for individuals without a putative disease-causing variant and a PRS_AF within the lowest-risk quintile. The absolute cumulative cardiomyopathy risk among study participants with both a putative disease-causing variant and a disease-specific PRS within the top-risk quintile ranged from 5.9% (UKB) to 15.2% (AoU) for DCM and from 11.7% (UKB) to 19.1% (AoU) for HCM.

Conclusions: Genetic variants that cause cardiomyopathy also increase the risk of AF, even in individuals without heart failure or overt ventricular disease. Combining disease-specific PRSs with these variants helps identify whether a person is more likely to develop atrial or ventricular disease. Although discovered as causes of cardiomyopathy, these genes often have an equal or greater impact on the risk of AF.

Keywords: atrial fibrillation; cardiomyopathy; genetics.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Roberts is supported by the Marianne Barrie/PHRI Chair in ARVC Research and the Canadian Institutes of Health Research. Dr McIntyre is supported by the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research. Dr Ware is supported by the Sir Jules Thorn Charitable Trust [21JTA], Medical Research Council (UK), British Heart Foundation [RE/24/130023; SP/17/11/32885], and the NIHR Imperial College Biomedical Research Centre. Drs Ware and Bezzina are supported by the Pathfinder Cardiogenomics programme of the European Innovation Council of the European Union [DCM-NEXT: 101115416]. Drs Ware and Watkins are supported by CureHeart, the British Heart Foundation’s Big Beat Challenge award (BBC/F/21/220106). Dr Ware has received research support from Bristol Myers Squibb; has acted as a paid advisor to MyoKardia, Pfizer, Foresite Labs, Health Lumen, Tenaya Therapeutics, and Solid Biosciences; and is a founder with equity in Saturnus Bio. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Cardiomyopathy Gene Variants and Polygenic Risk Scores in Atrial Fibrillation: Evidence for an Atrial-First Phenotype

Affiliations

Cardiomyopathy Gene Variants and Polygenic Risk Scores in Atrial Fibrillation: Evidence for an Atrial-First Phenotype

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources