Key result
High polygenic risk score linked to ~2.2-fold higher incident AF in women aged 60–69.
Why the study?
Polygenic risks for diseases are age-dependent, but sex differences in the age-related association between polygenic risk score and incident AF remained unclear.
Cohort (n=386,154)
Age-related genetic predisposition to atrial fibrillation exhibits distinct sex-specific patterns, with higher relative genetic risk in younger men and older women.
Background Polygenic risks for diseases are age‐dependent. However, sex differences in the age‐related association between polygenic risk score and incident atrial fibrillation (AF) remain unclear. Methods A prospective cohort study was conducted using UK Biobank data, including 386 154 participants aged 40 to 69 years, with a median follow‐up of 15.6 years. High AF polygenic risk score was defined as ≥0.858 (top quintile). Cox regression, 10‐fold cross‐validated C‐statistic, Royston's R 2 , and population‐attributable risk percentages were used to evaluate sex‐ and age‐specific genetic effects on incident AF. Results High polygenic risk score was significantly associated with incident AF, and continuous‐age analyses showed that the age‐related trajectories differed across sexes ( P for difference in age‐related trajectories=0.005). In age‐stratified analyses, the association was numerically higher in men aged 40 to 49 years (hazard ratio [HR], 2.76 versus 2.07 in women; Bonferroni‐adjusted P for interaction=0.077), whereas it was higher in women aged 60 to 69 years (HR, 2.22 versus 1.95 in men; Bonferroni‐adjusted P for interaction <0.001). Cross‐validated prediction analyses showed broadly similar age‐ and sex‐specific patterns. Population‐attributable risk of high polygenic risk score gradually declined across age strata in men, whereas it first increased and then decreased in women. Conclusions Age‐related genetic predisposition to AF exhibits distinct sex‐specific patterns, offering a foundation for personalized risk stratification and prevention strategies tailored to age and sex.
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Zhang et al. (2026) conducted a cohort in Incident atrial fibrillation (n=386,154). High AF polygenic risk score (≥0.858, top quintile) across sex and age strata vs. Lower AF polygenic risk score / comparison across sexes was evaluated on Incident atrial fibrillation (HR 2.22 in women vs HR 1.95 in men (aged 60-69 years), p=<0.001 for interaction (aged 60-69); 0.005 for sex difference in age-related trajectories).
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