Genomic Risk Prediction of Incident Atrial Fibrillation in Older Individuals Without Prior Cardiovascular Disease

Polygenic risk scores (PRSs) may enhance atrial fibrillation (AF) risk prediction when added to conventional risk factors. Most AF-PRS studies, however, focus on individuals with existing cardiovascular disease, rather than initially healthy older adults followed prospectively.

The objective of the study was to evaluate the predictive performance of a recent (2025) AF-PRS for incident AF in a cohort of healthy older individuals without prior cardiovascular events.

AF-PRS was calculated in 12,906 individuals aged ≥65 years without prior cardiovascular disease or AF at enrollment into the ASPREE (Aspirin in Reducing Events in the Elderly) trial. Cox proportional hazards models assessed HRs) per SD of AF-PRS, alone and with clinical risk factors (age, sex, body mass index, hypertension, diabetes, dyslipidaemia, thyroid-stimulating hormone, smoking, and alcohol). We compared AF-PRS to clinical scores (Cohorts for Heart and Aging Research in Genomic Epidemiology [CHARGE]-AF and hypertension, age, raised body mass index, male sex, sleep apnea, smoking, and Alcohol score[HARMS2-AF]). Model performance was evaluated using Harrell's C-index and likelihood ratio tests. Sex-stratified analysis was also conducted.

Over a median 4.5-years of follow-up, 654 incident AF cases occurred. AF-PRS was associated with incident AF (adjusted HR: 1.74 per SD; 95% CI: 1.58-1.84) (compared to CHARGE-AF [HR: 1.50] and HARMS2-AF [HR: 1.32] [all P < 0.0001]). Individuals in the highest AF-PRS quintile had 5.44-fold higher risk than those in the lowest (P < 0.0001). The AF-PRS showed stronger association in women than men (HR: 7.09 vs 4.51; interaction P = 0.007). AF-PRS improved prediction beyond clinical factors, increasing the C-index by 8.2% (0.63 → 0.71), 9.5% over CHARGE-AF (0.61 → 0.70), and 10.5% over HARMS2-AF (0.57 → 0.65).

The use of an AF-PRS improves risk prediction of incident AF above clinical risk factors in older individuals without cardiovascular disease.