DOI: 10.1161/jaha.126.049774 ISSN: 2047-9980

Sex Differences in the Associations of Age‐Related Genetic Predisposition With Incident Atrial Fibrillation: A Prospective Cohort Study

Feilong Zhang, Yuhao Hu, Liangchuan Chen, Pengfei Zheng, Yangye Xu, Chi Yuan, Zhou Du, Yangjing Xie, Zhenhua Lu, Xiaochen Wang, Zhen Dong, Ronghui Yu
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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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