Brain Connectivity Yields Insights into the Pathogenesis of Epilepsy and Subtypes: Evidence from Mendelian Randomization Analysis

<b>Background:</b> Alterations of brain connectivity within resting-state networks (RSNs) have been widely reported in observational studies on epilepsy. However, the causal relationship between epilepsy and structural connectivity (SC)/functional connectivity (FC) within RSNs remain unclear. We conducted a bidirectional two-sample Mendelian randomization (MR) to explore the causal relationship between epilepsy subtypes and brain connectivity properties within RSNs. <b>Methods:</b> Genetic instruments were obtained from the latest genome-wide association studies (GWAS) of 69,995 individuals (<i>N</i> _cases = 27,559, <i>N</i> _controls = 42,436) issued by the International League Against Epilepsy. The GWAS summary SC/FC data within RSNs (<i>N</i> _SC = 23,985, <i>N</i> _FC = 24,336) were sourced from the Center for Neurogenomics and Cognitive Research. We investigate the causal relationship between epilepsy subtypes and brain connectivity within RSNs through a bidirectional two-sample MR analysis. <b>Results:</b> We found that the increased risk of generalized genetic epilepsy is consistent with a causal effect on dorsal attention and somatomotor FC. In the reverse MR analysis, there was no suggestive causal effect of FC/SC connectivity on epilepsy subtypes. <b>Conclusions:</b> This study shed light on the associations of FC/SC levels within the RSNs and epilepsy along with its subtypes. This insight could yield crucial intervention strategies to different subtypes of epilepsy at the level of brain structure and functional networks.