Causal association between cerebral small vessel disease and epilepsy

Cerebral small vessel disease (SVD) is known to increase the risk of epilepsy, but the causal relationship between the two remains unclear. This study utilizes Mendelian Randomization (MR) to assess the genetic link between SVD and epilepsy, incorporating additional analyses including colocalization, gene-set, and pathway analysis to provide further evidence for shared mechanisms. We performed a two-sample MR study using 13 SNPs strongly associated with SVD as instrumental variables to assess their causal relationship with epilepsy. We also conducted colocalization analysis to identify shared genetic variants between SVD and epilepsy, gene-set enrichment analysis to explore common biological pathways, and protein-protein interaction (PPI) network analysis to investigate the molecular mechanisms. The MR analysis revealed a significant causal effect of SVD on epilepsy, with an odds ratio (OR) of 1.29 (95% CI: 1.09-1.53, P < 0.001). Colocalization analysis identified three genomic regions (chr1:100-600 kb, chr3:200-700 kb, and chr5:50-500 kb) with evidence of shared genetic variants. Pathway analysis highlighted endothelial cell signaling, blood-brain barrier function, and neuroinflammatory responses as enriched pathways, linking vascular health to neuronal excitability. The PPI network revealed key proteins involved in both vascular and neuronal processes, including ZNF646, PLEKHG1, and NOTCH3, further supporting shared mechanisms. This study provides strong genetic evidence for an association between SVD and epilepsy, with new insights from colocalization, gene-set, and pathway analyses while recognizing the limitations of Mendelian Randomization in establishing temporal causality. The findings suggest that genetic variants affecting vascular health, neuroinflammation, and blood-brain barrier integrity may contribute to both SVD and the risk of epilepsy. These results strengthen the understanding of the shared biological mechanisms underlying these two conditions and highlight SVD as an important risk factor for epilepsy.