Familial factors rather than paternal age contribute to the aetiology of epilepsy

Background Whether paternal age associated with offspring's epilepsy risk is a cause of de novo mutation as men age, or just an association due to confounding factors, is still unclear.Methods We performed a population-based, multi-generation and sibling comparison study in Taiwan, which included 2 751 232 singletons born in 2001-17 who were followed until 2020. Of these, 819 371/826 087 with information on paternal/maternal grandparents were selected for multi-generation analyses and 1 748 382 with sibling(s) were selected for sibling comparison. Cox proportional hazard regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI).Results In the total cohort, there was an increased risk of epilepsy in individuals with advanced paternal age, e.g. the HR for paternal age >= 50 was1.36 (95% CI: 1.15-1.61) compared with paternal age 25-29, and fathers older than mothers, e.g. the HR for parental age difference >= 15 years was 1.29 (95% CI: 1.16-1.43). When accounting for parental age difference, the association between paternal age and epilepsy in offspring was attenuated (HR for paternal age >= 50 was 1.11, 95% CI: 0.93-1.34). Multi-generation analyses did not support the association of advanced grand-paternal age at childbirth of the parent with offspring's risk of epilepsy. Sibling comparison analyses did not support the association of older paternal age with increased risk of epilepsy (HR was 0.96 for per year increase in paternal age, 95% CI: 0.96-0.97).Conclusions These results do not support the hypothesis that advanced paternal age is associated with epilepsy in offspring. Instead, familial factors may explain the observed paternal age association with the offspring's risk of epilepsy.