| Title: | Cardiomyopathy Gene Variants and Polygenic Risk Scores in Atrial Fibrillation Evidence for an Atrial-First Phenotype |
| Journal: | Journal of the American College of Cardiology |
| Published: | 18 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41706057/ |
| DOI: | https://doi.org/10.1016/j.jacc.2025.12.014 |
Publication 17722
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
BACKGROUND: Atrial fibrillation (AF) is heritable and its complex underlying genetic substrate is gradually being unraveled.</p>
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.</p>
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.</p>
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 PRSAF 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 PRSAF 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.</p>
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.</p>
17 Keywords
- Adult
- Aged
- Atrial Fibrillation
- Cardiomyopathies
- Cardiomyopathy, Hypertrophic
- Cohort Studies
- Female
- Genetic Predisposition to Disease
- Genetic Risk Score
- Genetic Variation
- Humans
- Male
- Middle Aged
- Multifactorial Inheritance
- Phenotype
- Risk Assessment
- Risk Factors
20 Authors
- Guilherme L da Rocha
- James Feiner
- Julieta Lazarte
- Keona Pang
- Yanran Li
- Ann Le
- Alice Man
- Nazia Pathan
- Richard P Whitlock
- Emilie P Belley-Côté
- David Conen
- Jorge A Wong
- William F McIntyre
- Jeff S Healey
- Connie R Bezzina
- Hugh Watkins
- James S Ware
- Rafik Tadros
- Guillaume Paré
- Jason D Roberts
1 Application
| Application ID | Title |
|---|---|
| 15255 | Identification of the shared biological and sociodemographic factors underlying cardiovascular disease and dementia risk |
Enabling scientific discoveries that improve human health