The causal impact of genetically predicted inflammatory bowel disease on extraintestinal manifestations: a mendelian randomization study

Background Extraintestinal manifestations (EIMs) significantly affect the life quality of people with inflammatory bowel disease (IBD) and are crucial factors impacting occurrence rates and mortality among IBD patients. This study performed a Mendelian randomization (MR) analysis to investigate the causal relationships between genetically predicted IBD and the development of EIMs, including erythema nodosum (EN), episcleritis, scleritis, uveitis, primary sclerosing cholangitis (PSC), and spondyloarthritis. To further investigate differences between subtypes, separate analyses were conducted for ulcerative colitis (UC) and Crohn's disease (CD). Methods The study was conducted based on genome-wide association studies (GWAS) data. We carefully selected SNPs associated with both exposure and outcome by comparing and integrating data from GWAS and relevant literature, and prioritizing studies with large sample sizes, high quality, and as much population homogeneity as possible. The SNPs associated with IBD, UC and CD were extracted from the International Inflammatory Bowel Disease Genetics Consortium. And the SNPs associated with EIMs were extracted from the UK Biobank, the International PSC Study Group and the FinnGen study. A series of quality control steps were taken in our analysis to select eligible instrumental SNPs which were strongly associated with exposure. The causal effects were estimated using a primary analysis that employed inverse-variance weighting (IVW) and complementary analysis that utilized MR-Egger weighted by the median. A sensitivity analysis was conducted using the Cochran Q statistic, a funnel plot, the MR-Egger intercept, and a leave-one-out approach. Reverse causality analysis was also performed to ensure the robustness of the findings. Furthermore, a fixed-effects meta-analysis was employed to combine MR outcomes from various data origins, bolstering the strength and dependability of our findings. Results Our findings indicated that genetically predicted IBD had a robust causal relationship with an increased risk of specific conditions, including EN (OR, 1.20; 95% CI, 1.09-1.32; p < 0.01), uveitis (OR, 1.15; 95% CI, 1.11-1.20; p < 0.01), PSC (OR, 1.21; 95% CI, 1.13-1.28; p < 0.01), and spondyloarthritis (OR, 1.19; 95% CI, 1.14-1.23; p < 0.01). In subgroup analyses, the causal effects of both UC and CD on EN, uveitis, PSC, and spondyloarthritis were also significant and robust. Additionally, no significant evidence of causality was observed between genetically predicted IBD, UC, and CD, and the occurrence of both episcleritis and scleritis. The results of reverse causality analysis indicated a robust causal association between genetically predicted PSC and the elevated risk of IBD (OR, 1.21; 95% CI, 1.15-1.29; p < 0.01), UC (OR, 1.27; 95% CI, 1.17-1.37; p < 0.01), and CD (OR, 1.10; 95% CI, 1.02-1.20; p < 0.01). Additionally, spondyloarthritis had a causal relationship with an increased risk of both IBD (OR, 1.03; 95% CI, 1.01-1.06; p < 0.01) and UC (OR, 1.05; 95% CI, 1.02-1.08; p < 0.01).