Genetic associations of cholelithiasis and biliary tract cancer

Biliary tract cancer (BTC) is highly malignant and more prevalent in populations with cholelithiasis, but the underlying mechanisms remain unclear. This study aimed to investigate the potential genetic links between cholelithiasis and BTC. We first employed single- and two-sample Mendelian randomization to assess whether the association between cholelithiasis and BTC incidence was influenced by confounding factors, revealing a significant association between cholelithiasis and BTC (P < 0.05). Multi-trait analysis of GWAS identified five novel lead genomic risk loci for BTC, with functional mapping and annotation performed using FUMA. Colocalization analysis using quantitative trait loci data highlighted shared signals for LRPPRC and ABCG5 in liver tissue. Additionally, in individuals without cholelithiasis, genetic loci rs6741243 and rs7599981 were associated with an increased BTC risk (both P < 0.05) in a Cox regression model. Gene expression analysis further supported these findings, showing significant upregulation of LRPPRC (P < 0.001) and downregulation of ABCG5 (P < 0.001) in BTC tissues, confirming their roles in carcinogenesis. This study provides compelling evidence for a genetic association between cholelithiasis and BTC, highlighting the role of genetic variants in ABCG5/8 and LRPPRC in mediating these conditions.