Genetic Prediction of Antiglycemic Drug Targets and Risk of Epilepsy: A Mendelian Randomization Study

Abstract

Diabetes has been linked to an increased risk of epilepsy in observational studies. The antiglycemic drugs have been shown in animal studies to improve seizures. However, whether the associations between antiglycemic drugs and epilepsy in human is not known. In this study, we conducted a Mendelian randomization investigation to assess the potential causal role of antiglycemic drug targets in epilepsy.We used the International League Against Epilepsy Data as the discovery set and FinnGen Data as the replication set .Three antidiabetic drug target genes, including ETFDH, CYP21A2, and CYP2D6 were discovered to be involved in epilepsy. ETFDH predicted as a target gene in the discovery set (IVW, OR = 1.018, 95% CI, 1.004–1.033, p = 0.009), replication set (IVW, OR = 1.074, 95% CI, 1.034–1.114, p = 0.00016) and CYP21A2 gene in the discovery set (IVW, OR = 1.029, 95% CI, 1.005– 1.053, p = 0.016) and replication set (IVW, OR = 1.057, 95% CI, 1.001–1.116, p = 0.045) showed a causal association with an increased risk of epilepsy. In contrast, the CYP2D6 gene was found to be a protective factor for epilepsy in both the discovery set (IVW, OR = 0.0984, 95% CI, 0.969–0.998, p = 0.025) and the replication set (IVW, OR = 0.977, 95% CI, 0.955–1.000, p = 0.046). By searching the pharmacological effects of anti-glucose drug target gene related drugs and binding drugs in DrguBank, Metformin was found to be ETFDH gene inhibitor, showing a potential therapeutic effect on epilepsy.