Gallbladder disease and colorectal cancer: a two-sample bidirectional Mendelian randomization study

OBJECTIVE: To assess whether a bidirectional causal relationship exists between gallbladder disease and colorectal cancer (CRC) using a two-sample, bidirectional Mendelian randomization (MR) approach based on genome-wide association study (GWAS) summary statistics. METHODS: We used European-ancestry data from the IEU OpenGWAS project within the UK Biobank. In the forward MR analysis, gallbladder disease was treated as the exposure and CRC as the outcome; in the reverse analysis, genetic liability to CRC was treated as the exposure and gallbladder disease as the outcome. The inverse variance weighted (IVW) method served as the primary analysis, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Instrument strength was evaluated using F statistics (F > 10 as the threshold for strong instruments). Sensitivity analyses included MR-Egger intercept tests for horizontal pleiotropy, Cochran's Q tests for heterogeneity, leave-one-out analyses, and visual inspection of funnel plots. RESULTS: In the forward analysis, 19 independent SNPs significantly associated with gallbladder disease were included, all with F statistics > 10. IVW analysis showed no significant causal association between gallbladder disease and CRC risk (odds ratio 95% confidence interval including 1, P > 0.05), and the results from MR-Egger, weighted median, and mode-based methods were directionally consistent. Some heterogeneity was observed, but there was no evidence of substantial horizontal pleiotropy, and leave-one-out and funnel plot analyses supported the robustness of the findings. In the reverse analysis, 30 SNPs associated with CRC were retained, again all with F statistics > 10. IVW and complementary MR methods consistently indicated no significant causal effect of genetic liability to CRC on the risk of gallbladder disease (P > 0.05), with no notable heterogeneity or pleiotropy detected and broadly stable sensitivity analysis results. CONCLUSION: This two-sample, bidirectional MR study found no evidence for a causal relationship in either direction between gallbladder disease and CRC, suggesting that gallbladder disease and its genetic susceptibility are unlikely to be major genetic drivers of colorectal carcinogenesis. Individuals should not be classified as high-risk for CRC solely on the basis of gallbladder disease or cholecystectomy history, although coexisting metabolic risk factors still warrant comprehensive management and further study.