Epilepsy concordance in monozygotic twins: the role of common genetic variants

Factors underlying discordance for epilepsy in monozygotic twins, in the absence of obvious acquired insults, are incompletely understood. Whilst subtle lesions and postzygotic mutations are sometimes observed, the contribution of common genetic variants remains unexplored. We investigated the role of these variants, measured by polygenic risk scores, in epilepsy concordance. We hypothesized that higher epilepsy polygenic risk scores in concordant monozygotic twins, compared to discordant monozygotic twins and controls, reflect increased epilepsy risk, raising the likelihood of both twins being affected. We calculated epilepsy polygenic risk scores for 102 monozygotic twin pairs (49 concordant, 53 discordant) and 14 632 controls using 2023 epilepsy genome-wide association study summary statistics. Logistic regression, adjusted for sex and principal ancestry components, showed that concordant pairs had significantly higher epilepsy polygenic risk scores than discordant pairs (mean 0.71 versus 0.18; Padj = 0.03) and controls (mean 0.71 versus 0; Padj = 0.001). In contrast, epilepsy polygenic risk scores in discordant pairs did not differ from controls (mean 0.18 versus 0; Padj = 0.38). Our findings suggest that concordance for epilepsy in monozygotic twins is partly driven by common genetic variant burden, underscoring the potential utility of epilepsy polygenic risk scores as predictive markers for epilepsy risk in the general population.