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Novel insights into modifiable risk factors of cholelithiasis: A Mendelian randomization study. BACKGROUND & AIMS: The risk factors of cholelithiasis have not been clearly identified, especially for total cholesterol. Here, we try to identify these causal risk factors. APPROACH & RESULTS: We obtained genetic variants associated with the exposures at the genome-wide significance (p < 5x10-8 ) level from corresponding genome-wide association studies (GWAS). Summary-level statistical data for cholelithiasis were obtained from FinnGen and UK Biobank (UKB) consortia. Both univariable and multivariable Mendelian randomization (MR) analyses were conducted to identify causal risk factors of cholelithiasis. Results from FinnGen and UKB were combined using fixed effect model. In FinnGen, the odds of cholelithiasis increased per 1-SD increase of body mass index (BMI) (OR = 1.631, P = 2.16 x 10-7 ), together with body fat percentage (OR = 2.108, P = 4.56 x 10-3 ) and fasting insulin (OR = 2.340, P = 9.09 x 10-3 ). The odds of cholelithiasis would also increase with lowering of total cholesterol (OR = 0.789, P = 8.34 x 10-5 ) and low-density lipoprotein cholesterol (LDL-C) (OR = 0.792, P = 2.45x10-4 ). However, LDL-C was not significant in multivariable MR. In UKB, the results of BMI, body fat percentage, total cholesterol and LDL-C were replicated. In meta-analysis, the liability to type 2 diabetes mellitus and smoking could also increase the risk of cholelithiasis. Besides, there were no associations with other predominant risk factors. CONCLUSIONS: Our MR study corroborated the risk factors of cholelithiasis from previous MR studies. Furthermore, lower total cholesterol level could be a novel independent risk factor.