Proteome-wide Mendelian randomization implicates causal plasma proteins in epilepsy

Objective
Proteomic changes can provide critical insights into the molecular alterations underlying epilepsy. Recent advances in proteomic technologies present opportunities to identify novel biomarkers and therapeutic targets.
Methods
To investigate the causal relationships between plasma protein levels and the risk of epilepsy and its subtypes, we performed a proteome-wide Mendelian randomization meta-analysis utilizing data from large genome-wide association studies. Pathway enrichment analysis was further conducted to identify pathways implicated in the pathogenesis of epilepsy.
Results
Our study provided evidence of causal associations between two proteins (GZMA and TFF1) and an increased risk of epilepsy, as well as three proteins (SHBG, CCL15, and ACE) and a reduced risk of the disease. Additionally, CCL15 and NQO1 were associated with a lower risk of focal epilepsy, whereas GZMA was associated with an increased risk of focal epilepsy. For generalized epilepsy, a total of 16 proteins showed significant associations. Pathway enrichment analysis implicated the regulation of binding, response to electrical stimulus, and glycosaminoglycan binding in the disease pathogenesis.
Conclusion
The identified proteins represent promising biomarkers for early diagnosis and novel targets for therapeutic intervention, though their clinical translation requires further experimental validation and functional characterization.