Proteome-Wide Mendelian Randomization Reveals Novel Protein Targets for Epilepsy

Epilepsy affects over 70 million individuals globally and remains inadequately managed by current antiepileptic drugs, which often present limited efficacy and adverse effects. This study aims to identify novel, safer, and more effective therapeutic targets for epilepsy using a proteome-wide Mendelian randomization (MR) approach. Using MR, we evaluated causal relationships between plasma proteins and epilepsy and its subtypes risk, integrating protein quantitative trait loci data with genome-wide association study findings. Further validation included: phenome-wide MR to assess specificity, enrichment analysis for functional insights, mediation MR to explore underlying pathways, and protein-protein interaction (PPI) network construction. We identified 29 plasma proteins with putative causal effects on epilepsy and its subtypes. Through phenome-wide MR, we prioritized 6 candidates for all epilepsy, 1 for focal epilepsy, and 12 for generalized epilepsy, each exhibiting favorable safety profiles. These proteins showed minimal associations with non-epilepsy diseases and functionally interacted with known antiepileptic drug targets. Mediation MR revealed that plasma metabolites accounted for 1.6%-22.3% of the total protein effects on epilepsy risk, highlighting the role of metabolic pathways. These findings provide strong evidence for novel protein targets with potential therapeutic relevance, some of which mediate their effects through metabolic processes. The functional overlap with existing drug targets further supports their translational value. This study identifies promising protein targets for epilepsy treatment with high specificity and mechanistic relevance, offering new directions for drug development and precision medicine.