Abstract
OBJECTIVE: This study aims to investigate the causal relationship between cathepsins and epilepsy, using Mendelian randomization (MR) and mediation analysis. METHODS: Publicly accessible summary statistics on epilepsy were obtained from FinnGen and the International League Against Epilepsy Consortium. Cathepsin genome-wide association data were provided by the IEU OpenGWAS. To evaluate the causal relationship between epilepsy and cathepsins, we conducted a bidirectional two-sample Mendelian randomization (MR) and mediation analysis. RESULTS: The results of the MR analysis revealed that elevated cathepsin E levels correlated with a higher likelihood of developing generalized epilepsy (odds ratio: 1.304, 95% confidence interval: 1.127-1.508, p: 0.0004, p adjusted for false discovery rate: 0.044). The mediation analysis identified a disintegrin and metalloproteinase with thrombospondin motifs 4 as having a notable impact (mediation effect: 23.5%) in the causal link between cathepsin E and generalized epilepsy. SIGNIFICANCE: This study provides evidence of a causal relationship between cathepsin E and generalized epilepsy, suggesting that elevated cathepsin E levels may increase the risk of developing this condition. The identification of a disintegrin and metalloproteinase with thrombospondin motifs 4 as a mediator offers insight into the molecular mechanisms underlying this association, which could guide future research into potential therapeutic targets for epilepsy. PLAIN LANGUAGE SUMMARY: Epilepsy is a common neurological disorder, but some patients do not respond to standard treatments. This study looks at a protein family called cathepsins and how they might be linked to epilepsy. We found that higher levels of cathepsin E are associated with a higher chance of generalized epilepsy. Our results suggest that cathepsin E could play a key role in causing epilepsy, which could lead to new treatment options for patients who do not respond to current therapies.