Causal relationships between epilepsy and the microstructure of the white matter: A Mendelian randomization study

To examine the causal bidirectional relationships between epilepsy and microstructural changes in the white matter (WM). A genome-wide association study meta-analysis of the International League Against Epilepsy Consortium on Epilepsy and 360 WM imaging-derived phenotypes (IDPs) from the UK Biobank was used for the analysis. Genetic correlation analyses were conducted based on summary statistics of various "IDP-epilepsy" pairs for 2-sample Mendelian randomization (MR) analysis to explore the causal relationships. We used the inverse variance weighted (IVW) method as the primary MR analysis approach, and conducted sensitivity analyses for pleiotropy and heterogeneity. Forward MR analysis revealed that alterations in the 16 WM IDPs increased the risk of epilepsy (q value < 0.05). Changes in the 38 WM IDPs were associated with a decreased risk of epilepsy (q value < 0.05). In the reverse analysis, seizures from all epilepsy types changed 5 WM IDPs, whereas seizures from juvenile myoclonic epilepsy altered 11 WM IDPs (q value < 0.05). This study revealed causal associations between changes in the WM microstructure and epilepsy subtypes. These findings offer new directions for early prevention and treatment of epilepsy.