Shared genetic architecture and mendelian randomisation between simvastatin-related medication use and cholelithiasis: a multi-method GWAS-based analysis

Introduction Statins are widely prescribed, but their relationship with cholelithiasis (CL) remains uncertain. We evaluated shared genetic architecture and MR associations between CL and UK Biobank medication-use phenotypes for simvastatin (SIM) and cholesterol-lowering medication (LLA). Material and methods GWAS summary statistics were analysed using LDSC, Genomic SEM, MAGMA, univariable MR, lipid-adjusted multivariable MR (MVMR), and cis-drug-target MR for HMGCR, NPC1L1, and PCSK9. MVMR adjusted SIM and LLA separately for LDL-C, HDL-C, and triglycerides. Results CL showed inverse genetic correlations with SIM (rg = –0.277, p = 1.54 × 10–4) and LLA (rg = –0.223, p = 2.47 × 10–3). Gene and pathway analyses implicated cholesterol–bile acid metabolism and enterohepatic signalling. On the native linear-model outcome scale, univariable MR supported an inverse SIM association ( = –0.050, 95% CI: –0.077 to –0.023, p < 0.001), whereas LLA was not significant (β = –0.029, 95% CI: –0.062 to 0.004, p = 0.090). MVMR direct effects were near null for SIM (β = 0.0051, p = 0.858) and LLA (β = 0.0060, p = 0.631), with conditional F-statistics < 10 and marked heterogeneity. Cis-drug-target MR showed no clear association for HMGCR, NPC1L1, or PCSK9. Conclusions Genetic liability to simvastatin medication use was modestly inversely associated with CL in univariable MR but not after lipid adjustment. Together, these findings support a potential protective genetic relationship between simvastatin-related medication use and CL and highlight lipid-related and target-specific mechanisms for further mechanistic and clinical validation.