Variability in epilepsy polygenic risk prediction across Taiwanese population and clinical cohorts

Objective: This study was undertaken to evaluate the predictive, stratification, and prognostic utility of polygenic risk scores (PRSs) for epilepsy in three Taiwanese cohorts comprising more than 7000 cases among more than 600 000 individuals, thereby addressing the limited evidence on PRS performance in non-European populations. Methods: Leveraging results from the latest multiancestry genome-wide association study (GWAS), we calculated PRS for all epilepsy, genetic generalized epilepsy (GGE), and focal epilepsy (FE) in two population cohorts—Taiwan Biobank–National Health Insurance Research Database (TWB-NHIRD; N ~ 105 K) and Taiwan Precision Medicine Initiative (TPMI; N ~ 500 K), with cases defined by International Classification of Diseases codes and medications—and a clinically ascertained sample (Taiwanese subset of the Epi25 consortium [Epi25-TWN]; N = 1140). PRS performance was assessed through lifetime risk models, age-at-onset stratifications, and phenome-wide association studies (PheWASs). Results: PRS performance varied substantially by cohort, epilepsy type, and age at onset. GGE PRS had the strongest effect on GGE in Epi25-TWN (per-unit odds ratio [OR] = 1.65 [95% confidence interval (CI) = 1.24–2.23], p = 8.3 × 10−4, R2 = 3.2%) but a weaker effect in TWB-NHIRD and TPMI (ORs = 1.09–1.13 [95% CI =.98–1.23], p =.002–.057, R2 =.14%–.22%). FE PRS effects on FE were more consistent but modest (ORs = 1.02–1.16 [95% CI =.97–1.33]). No prognostic value of PRS was found in predicting epilepsy from syncope or unspecified seizures. Individuals in the top 5% GGE PRS had >4-fold increased risk in Epi25-TWN but <1.5-fold in the others. Restricting to earlier onset cases strengthened PRS signals in population cohorts, particularly for GGE, with PheWAS analysis revealing epilepsy-specific associations. PRS effects were generally comparable but attenuated relative to European studies. Significance: Cohort design and phenotyping accuracy strongly influence the assessment of the predictive value of epilepsy PRS, highlighting caution in clinical interpretation. Incorporating richer phenotypic data and more diverse GWASs will be crucial to enhancing its applicability and clinical potential.