Variant-to-gene-mapping analyses reveal a role for the hypothalamus in genetic susceptibility to inflammatory bowel disease

ABSTRACT Background & Aims Inflammatory bowel disease (IBD) is a polygenic disorder principally characterized by dysregulated inflammation impacting the gastrointestinal tract. However, there is also increasing evidence for a clinical association with stress and depression. Given the role of the hypothalamus in stress responses and in the pathogenesis of depression, useful insights could be gleaned from understanding its genetic role in IBD. Methods We conducted genetic correlation analyses on publicly available GWAS summary statistics for depression and IBD traits to identify genetic commonalities. We used partitioned LD score regression, leveraging our ATAC-seq and promoter-focused Capture C data, to measure enrichment of IBD SNPs within promoter-interacting open chromatin regions of hESC-derived hypothalamic-like neurons (HNs). Using the same datasets, we performed variant-to-gene mapping to implicate putative IBD effector genes in HNs. To contrast these results, we similarly analyzed 3D genomic data generated in epithelium-derived colonoids from rectal biopsies from donors without pathologic disease noted at the time of colonoscopy. Finally, we conducted enrichment pathways analyses on the implicated genes to identify putative IBD dysfunctional pathways. Results We found significant genetic correlations (rg) of 0.122 with an adjusted P=1.4x10-4 for IBD: rg=0.122; Padj= 2.5x10-3 for ulcerative colitis and rg=0.094; Padj=2.5x10-3 for Crohn’s disease, and significant ∼4-fold (P = 0.005) and ∼7-fold (P = 0.03) enrichment of IBD SNPs in HNs and colonoids respectively. We implicated 25 associated genes in HNs, among which CREM, CNTF and RHOA encode key regulators of stress. Seven genes were also additionally implicated in the colonoids. We observed an overall enrichment for immune and hormonal signaling pathways, and a colonoid-specific enrichment for microbiota-relevant terms. Conclusions Our results suggest that the hypothalamus warrants further study in the context of IBD pathogenesis