The Causal Association of Irritable Bowel Syndrome with Multiple Disease Outcomes: A Phenome-Wide Mendelian Randomization Study

Background: This study aimed to identify novel associations between irritable bowel syndrome (IBS) and a broad range of outcomes. Methods: In total, 346,352 white participants in the U.K. Biobank were randomly divided into two halves, in which a genome-wide association study (GWAS) of IBS and a polygenic risk score (PRS) analysis of IBS using GWAS summary statistics were conducted, respectively. A phenome-wide association study (PheWAS) based on the PRS of IBS was performed to identify disease outcomes associated with IBS. Then, the causalities of these associations were tested by both one-sample (individual-level data in U.K. Biobank) and two-sample (publicly available summary statistics) Mendelian randomization (MR). Sex-stratified PheWAS-MR analyses were performed in male and female, separately. Results: Our PheWAS identified five diseases associated with genetically predicted IBS. Conventional MR confirmed these causal associations between IBS and depression (OR: 1.07, 95%CI: 1.01-1.14, p = 0.02), diverticular diseases of the intestine (OR: 1.13, 95%CI: 1.08-1.19, p = 3.00 x 10(-6)), gastro-esophageal reflux disease (OR: 1.09, 95%CI: 1.05-1.13, p = 3.72 x 10(-5)), dyspepsia (OR: 1.21, 95%CI: 1.13-1.30, p = 9.28 x 10(-8)), and diaphragmatic hernia (OR: 1.10, 95%CI: 1.05-1.15, p = 2.75 x 10(-5)). The causality of these associations was observed in female only, but not men. Conclusions: Increased risks of IBS is found to cause a series of disease outcomes. Our findings support further investigation on the clinical relevance of increased IBS risks with mental and digestive disorders.