Evaluation of the causal effects of blood metabolites on irritable bowel syndrome: Mendelian randomization.

ABSTRACT

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain, discomfort, and changes in bowel habits. The mechanism underlying IBS remains unclear, and little evidence exists for clarifying the causal relationship between blood metabolites and IBS. METHODS: We conducted a Mendelian randomization (MR) study using two samples. Exposure data for 7824 Europeans were extracted from a genome-wide association study (GWAS) on metabolite levels. The IBS GWAS data from the GWAS database were used for the initial analysis. The primary analysis of causal relationships was conducted using inverse-variance weighting (IVW) with MR-Egger and weighted medians as supplementary analyses. Sensitivity analyses were performed using a combination of the Cochran's Q test, MR-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier, and leave-one-out analysis. For significant associations, replication and meta-analyses were performed using additional independent IBS case GWAS data released by the FinnGen Consortium R9. To identify the metabolites, score regression, confounding analysis, and reverse MR were performed to further assess the causal relationships between the metabolites. RESULTS: After rigorous screening, we identified four known metabolites to be associated with IBS (stearate, odds ratio [OR] 0.74, 95% confidence interval [CI] 0.59-0.92; arginine, OR 1.36, 95% CI 1.07-1.74; 1-palmitoylglycerol, OR1.49, 95% CI 1.07-2.07; 1-palmitoylglycerophosphoinositol, OR 0.84, 95% CI 0.71-0.99). CONCLUSIONS: MR analysis revealed a causal relationship between the four metabolites and IBS, providing preliminary evidence for the pathogenesis of IBS. Our results provide novel insights into the potential biomarkers of IBS.