Mendelian randomization approach shows no causal effects of gestational age on epilepsy in offspring

Observational studies have suggested that gestational age was associated with the risk of epilepsy later in life. However, it remains unclear whether the association is of a causal nature. Two-sample Mendelian randomization (MR) was performed to assess the causal effect of fetal gestational age on epilepsy. Genome-wide association studies (GWAS) summary statistics of gestational duration, early preterm birth, preterm birth, and postterm birth were from the Early Growth Genetics (EGG) Consortium. GWAS summary-level data on epilepsy were obtained from the International League Against Epilepsy Consortium (ILAEC) and FinnGen Consortium. The inverse-variance weighted (IVW) was applied as the primary method to calculate estimates, which were further validated using other sensitivity analyses. There was not yet strong evidence of causal associations between gestational age and epilepsy of ILAEC (early preterm birth: odds ratio [OR]=1.01, 95% CI: 0.99–1.03, P = 0.441; preterm birth: OR=1.01, 95% CI: 0.96–1.07, P = 0.617; postterm birth: OR=0.96, 95% CI: 0.89–1.04, P = 0.357; gestational duration: OR=0.90, 95% CI: 0.75–1.07, P = 0.214). Similar results were obtained in the replication stage using epileptic samples from the FinnGen Consortium. Finally, a meta-analysis of the causal estimates from the ILAEC and FinnGen Consortium showed consistent results. No obvious pleiotropy was found throughout the MR study. The present study indicated that gestational age, either preterm birth or postterm birth, might not be causally associated with the risk of epilepsy. Further studies are warranted to evaluate the potential mechanisms underlying the epidemiological relationship between preterm birth and epilepsy.