The multi-omics insights into mitochondrial dysfunction in the pathogenesis of cholelithiasis.

Cholelithiasis is the most prevalent biliary disease globally, and mitochondrial dysfunction has been implicated in its pathogenesis. However, the exact mechanisms remain poorly understood. In this study, we used Summary-data-based Mendelian randomization (SMR) and colocalization analysis, integrating multi-omics data, to investigate the association between mitochondrial-related genes and cholelithiasis. Summary-level quantitative trait loci (QTL) data at methylation, RNA, and protein levels were retrieved from European cohort studies. We integrated multi-omics data, including methylation QTL (mQTL), expression QTL (eQTL), and protein QTL (pQTL), alongside genome-wide association studies (GWAS) data from FinnGen and the UK Biobank. SMR and colocalization analysis were employed to evaluate the causal relationship between mitochondrial-related genes and cholelithiasis. Potential therapeutic targets for cholelithiasis were further validated through phenome-wide association studies (PheWAS), functional enrichment analysis, protein-protein interaction networks (PPI), drug prediction, and molecular docking. Following integration of the multi-omics evidence, we identified 4 mitochondrial-related genes, categorized by evidence strength as: Tier 1 genes (supported by 2 omics and colocalization evidence): LIAS, HEBP1, PNKD; Tier 2 genes (supported by 2 omics): TARS2. PheWAS analysis indicated that these 4 genes were not associated with other traits. Biologically, these genes are closely related to metabolic processes. Molecular docking analysis showed high binding affinities for candidate drugs, including olmesartan and neostigmine bromide. By integrating multi-omics data, we have constructed the first causal chain of linking mitochondrial-related genes, metabolic pathways, and cholelithiasis. This study provides a theoretical foundation for personalized therapies targeting the genes LIAS, TARS2, HEBP1, and PNKD.