Immune-cell-specific genetic drivers of cholelithiasis revealed by single-cell transcriptome-wide Mendelian randomization and colocalization

Abstract Cholelithiasis is a common hepatobiliary disorder with limited pharmacological treatments due to poorly understood molecular mechanisms. We integrated single-cell expression quantitative trait loci (sc-eQTL) from 14 immune cell types with Mendelian randomization and Bayesian colocalization to identify causal genes associated with gallstone disease. Using two large GWAS cohorts totaling over one million individuals, we identified 56 robust immune-cell-specific eGenes, including TMEM258 , ITCH , DAGLB , and UBE2Q2 . Colocalization analysis revealed 28 eGenes with shared causal variants influencing both gene expression and disease risk. Functional enrichment highlighted roles in ER stress, lipid metabolism, ubiquitination, and immune signaling. Distinct gene signatures were observed across CD4 + and CD8 + T cells, B cells, and NK cells, revealing diverse immune mechanisms. These findings provide novel insights into the immunogenetic basis of cholelithiasis and offer a framework for identifying precision therapeutic targets in hepatobiliary diseases.