Copy number variation-based gene set analysis reveals cytokine signalling pathways associated with psychiatric comorbidity in patients with inflammatory bowel disease

Background: Recent studies discovered many genetic variants associated with both psychiatric and inflammatory disorders, but the role of genetic factors in the development of psychiatric comorbidity (PC) in inflammatory bowel disease (IBD) is underexplored. Particularly, it has been shown that some of the genetic variants have been linked to the concentrations of circulating cytokines and symptoms of the inflammatory cytokine-associated depression. We analysed genomic features of individuals with IBD by comparing IBD patients with PC with those who have IBD but without PC. We hypothesized that cytokine related signalling pathways may be significantly associated with the psychiatric comorbidity in patients with IBD.

Methods: Individuals enrolled in the Manitoba IBD Cohort Study were separated to two groups accordingly to the presence of PC. A sample set comprising 97 IBD individuals with PC (IBD + PC) and 146 IBD individuals without PC (IBD) was first used to identify copy number variations (CNVs) from genome-wide genetic data using three different detection algorithms. IBD + PC and IBD groups were compared by the number of CNVs overlapping each gene; deletions and duplications were analysed separately. Gene set overrepresentation analysis was then conducted using CNV-overlapped genes and the candidate gene sets of neurological and immunological relevance.

Results: Medium-sized CNV (size between 100 and 500 kilobase pairs)-burden is significantly higher in IBD + PC than IBD groups. Gene-based CNV association analysis did not show significant differences between the two IBD groups. Gene set overrepresentation analysis demonstrated the significant enrichment of gene sets related to cytokine signalling pathways by the genes overlapped by deletions in the IBD individuals with PC.

Conclusion: Our results confirm the role of cytokine signalling pathways in the development of PC in IBD. Additionally, our results warrant further study with a larger sample size focusing on cytokine SNPs to further understand the relationship between inflammatory and psychiatric disorders.