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

Area of Science:

• Genetics and Genomics
• Mitochondrial Biology
• Biliary System Diseases

Background:

• Cholelithiasis (gallstones) is a common global health issue.
• Mitochondrial dysfunction is suspected in gallstone formation, but mechanisms are unclear.

Purpose of the Study:

• To investigate the causal link between mitochondrial-related genes and cholelithiasis.
• To identify potential therapeutic targets for gallstone disease.

Main Methods:

• Integrated multi-omics data (mQTL, eQTL, pQTL) with GWAS data.
• Employed Summary-data-based Mendelian randomization (SMR) and colocalization analysis.
• Validated findings using PheWAS, PPI networks, and molecular docking.

Main Results:

• Identified four key mitochondrial genes (LIAS, HEBP1, PNKD, TARS2) causally associated with cholelithiasis.
• These genes are involved in metabolic processes and show no association with other traits.
• Molecular docking identified potential drugs like olmesartan for therapeutic intervention.

Conclusions:

• Established the first causal chain linking mitochondrial genes, metabolism, and cholelithiasis.
• Provides a genetic and molecular basis for developing personalized gallstone therapies targeting LIAS, TARS2, HEBP1, and PNKD.