Evidence for genetic correlation between appendix and inflammatory bowel disease: a bidirectional Mendelian randomization study

Abstract

Observational studies highlighted an association between the appendix and inflammatory bowel disease (IBD). However, it's unclear whether the identified association is causal because of difficulties in establishing a clear temporal sequence. We investigated the association between acute appendicitis, appendectomy, and IBD by using two-sample bidirectional univariable Mendelian randomization (UVMR), multivariable MR (MVMR) and linkage disequilibrium score regression (LDSC) analyses. Eligible instrumental variables were screened from previous genome-wide association studies (GWAS) of European ancestry for analysis. The inverse variance-weighted (IVW) method was used for the primary analysis. Sensitivity analyses were used to detect and correct pleiotropy. LDSC analysis determined SNP-based heritability (h2) for acute appendicitis, IBD, Crohn's disease (CD), and ulcerative colitis (UC). Following that, cross-trait LDSC analysis assessed genetic correlations (rg) between these traits using GWAS summary data. Genetically predicted UC was associated with a significantly lower risk of acute appendicitis (OR = 0.933, P < 0.001) and appendectomy (OR = 0.954, P < 0.001), but conversely, acute appendicitis or appendectomy had no causal effect on IBD, UC or CD (all P > 0.05). CD had a suggestive association with appendectomy (OR = 0.981, P = 0.018) but was not significant after excluding the effect of UC by MVMR (OR = 0.999, P = 0.889). Furthermore, LDSC suggested a negative genetic correlation between UC and acute appendicitis (rg = -0.205, P = 0.005). In conclusion, our study confirms UC casually leads to a decreased risk of acute appendicitis and appendectomy, but neither acute appendicitis nor appendectomy reduces the risk of IBD, UC, and CD.