Atrial fibrillation (AF) has a complex genetic architecture, and a new study suggests that integrating information on common, rare, and somatic genetic variants can significantly improve risk prediction. Researchers developed an integrated genomic model (IGM-AF) that, when combined with clinical factors, enhanced the stratification of individuals at risk for incident AF.¹
This cohort study analysed whole-genome sequence data from the UK Biobank.¹ The study included 416,085 individuals (mean age 56.6 years; 54.0% female) who were followed for incident AF events.
The investigators developed the IGM-AF, which comprised three genetic components: a polygenic risk score (PRS) for common variants, a composite rare variant gene set (AFgeneset), and somatic variants associated with clonal haematopoiesis of indeterminate potential (CHIP). The predictive performance of this model was assessed against and in combination with the established clinical risk model, the Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) score. The primary outcome was the hazard ratio (HR) for 5-year incident AF.
All three genetic components were independently associated with a higher risk of incident AF. The PRS was associated with an HR of 1.65 per standard deviation (95% CI, 1.63–1.67). The AFgeneset had an HR of 1.63 (95% CI, 1.52–1.75), and CHIP had an HR of 1.26 (95% CI, 1.15–1.38).
The study found a cumulative effect of these genetic drivers. The 5-year cumulative incidence of AF was at least two-fold higher among individuals who had all three genetic drivers compared with those who had only one.
When the IGM-AF was integrated with the clinical CHARGE-AF model, it demonstrated superior predictive performance (C statistic, 0.80; 95% CI, 0.80–0.80) compared to either model alone. The addition of the genomic model also improved the classification of the at-risk population (net reclassification index, 0.08; 95% CI, 0.07–0.09).
The findings highlight the distinct and complementary roles that common, rare, and somatic variants play in the development of AF. The study authors concluded that their results “demonstrated the complementary value of common, rare, and somatic variants in shaping genomic AF risk,” and suggested that “leveraging comprehensive genetic information may enhance screening and preventive interventions for AF.”¹ This integrated approach could lead to more personalised risk stratification and earlier implementation of preventive strategies for individuals at high genetic risk.
References
1. Zhang R, Kim MS, Yin W, et al. Contributions of Common, Rare, and Somatic Genetic Variants to Incidence of Atrial Fibrillation. JAMA Cardiol. Published online 8 October 2025. https://doi.org/10.1001/jamacardio.2025.3664
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