Inflammatory Bowel Disease and Rheumatoid Arthritis Share a Common Genetic Structure

Background: The comorbidity rate of inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) is high; nevertheless, the reasons behind this high rate remain unclear. Their similar genetic makeup probably contributes to this comorbidity.

Methods: Based on data obtained from the genome-wide association study of IBD and RA, we first assessed an overall genetic association by performing the linkage disequilibrium score regression (LDSC) analysis. Further, a local correlation analysis was performed by estimating the heritability in summary statistics. Next, the causality between the two diseases was analyzed by two-sample Mendelian randomization (MR). A genetic overlap was analyzed by the conditional/conjoint false discovery rate (cond/conjFDR) method.LDSC with specific expression of gene analysis was performed to identify related tissues between the two diseases. Finally, GWAS multi-trait analysis (MTAG) was also carried out.

Results: IBD and RA are correlated at the genomic level, both overall and locally. The MR results suggested that IBD induced RA. We identified 20 shared loci between IBD and RA on the basis of a conjFDR of <0.01. Additionally, we identified two tissues, namely spleen and small intestine terminal ileum, which were commonly associated with both IBD and RA.

Conclusion: Herein, we proved the presence of a polygenic overlap between the genetic makeup of IBD and RA and provided new insights into the genetic architecture and mechanisms underlying the high comorbidity between these two diseases.