Paternal valproate use and impact of shared genetic susceptibility on child neurodevelopment

Paternal use of valproate during spermatogenesis has been associated with increased risk of neurodevelopmental disorders (NDDs) in offspring, yet the role of genetic confounding is unclear. Using data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), we assessed genetic susceptibility to epilepsy, ADHD and autism spectrum disorders (ASD) in fathers with epilepsy treated with valproate (n = 41), lamotrigine or levetiracetam (n = 37), other anti-seizure medications (ASMs; n = 80), and healthy controls (n = 54,752). Fathers using valproate had significantly higher polygenic risk scores (PRSs) for epilepsy compared to those using lamotrigine or levetiracetam (mean difference: 0.66, 95% CI: 0.21-1.11, p ≈ 0.005), other ASMs (0.41, 95% CI: 0.02-0.81, p ≈ 0.04) and controls (0.85, 95% CI: 0.54-1.15, p = 5.8 × 10⁻⁸). No robust associations were found between paternal ASM use or epilepsy PRS and child neurodevelopmental outcomes. Significant genetic overlap was found among the top 1% of weighted SNPs in the PRSs for epilepsy, ADHD and ASD (428 genes, p ≈ 0.0001), enriched for neurodevelopmental pathways. These results emphasize the importance of considering shared genetic susceptibility when assessing risks of paternal valproate exposure.