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CLINICAL RESEARCH
Shared genetic architecture and mendelian randomisation between simvastatin-related medication use and cholelithiasis: a multi-method GWAS-based analysis
1
GCP Office, The First People’s Hospital of Shuangliu District (West China Airport Hospital of Sichuan University), Chengdu, China
2
Department of Gastroenterology, The First People’s Hospital of Shuangliu District (West China Airport Hospital of Sichuan University), Chengdu, China
Submission date: 2026-04-14
Final revision date: 2026-08-07
Acceptance date: 2026-09-24
Online publication date: 2026-10-21
Corresponding author
Xin Zhang
Department of Gastroenterology The First People’s Hospital of Shuangliu District (West China Airport Hospital of Sichuan University) 120, Chengbei Shangjie St Dongsheng Town Shuangliu District Chengdu 610200, China
Department of Gastroenterology The First People’s Hospital of Shuangliu District (West China Airport Hospital of Sichuan University) 120, Chengbei Shangjie St Dongsheng Town Shuangliu District Chengdu 610200, China
KEYWORDS
cholelithiasissimvastatincholesterol-reducing agentsmedication-use phenotypedrug-target Mendelian randomisationgenetic correlationgenomic SEMMAGMAbile acid metabolismFXR signalling
TOPICS
ABSTRACT
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.
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.
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| ISSN: | 1734-1922 |
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