Identifying potential drug targets for postoperative abdominal wall hernia using Mendelian randomization: a multi-omics study

This study aims to identify potential drug targets for postoperative abdominal wall hernia. Mendelian Randomization (MR) was applied to integrate data from druggable gene libraries, cis-pQTL data, and cis-eQTL data to analyze postoperative abdominal wall hernia in the FinnGen R11 population. Sensitivity and heterogeneity tests were conducted, along with reverse causality validation, to explore potential drug targets. A colocalization analysis was performed based on three cis-pQTL databases and cis-eQTL databases. Linkage disequilibrium was verified using Summary Data-Based Mendelian Randomization (SMR), and potential drug side effects were assessed using existing databases. Finally, drug target predictions and molecular docking studies were conducted. MR analysis revealed that, within the druggable target range, only one druggable gene, cathepsin S (CTSS) (FDR < 0.05; OR = 1.13, 95% CI = 1.06-1.20, P = 6.79 × 10e-5), was positively correlated with postoperative abdominal wall hernia. Colocalization analysis showed PPH4 > 0.7 in the cis-pQTL and cis-eQTL gene window of ± 50 kb. A key variant (rs41305070) was identified. Evaluation of drug side effects and molecular docking demonstrated that CTSS holds potential as a promising druggable target. Elevated levels of CTSS increase the risk of postoperative abdominal wall hernia, making CTSS a promising therapeutic target for this condition.