Abstract
A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD.
Highlights
This immune network reflects the existing states of knowledge related to the immune component of the inflammatory bowel disease (IBD) network and so was chosen to serve as a seed set of genes that could be used to identify a homologous set of genes in an IBD-tissue-specific context
To define this IBD-tissue-specific context, we used gene expression data generated from intestinal tissues isolated from three independent populations of patients with IBD representing different stages of disease: treatment-naive pediatric patients (RISK cohort)[11], patients refractory to anti–tumor necrosis factor (TNF)-α treatment who have participated in an ustekinumab clinical trial (CERTIFI cohort)[12,13], and patients with advanced disease (Supplementary Table 1)
When comparing the expression of Crohn's disease and ulcerative colitis genome-wide association studies (GWAS) genes in data from non-inflamed and inflamed tissues across different intestinal regions from the CERTIFI population, we found distinct cell-type-specific enhancer regions significantly enriched for variants associated with Crohn's disease and ulcerative colitis (Supplementary Fig. 2 and Supplementary Tables 5–7)
Summary
Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. These homologous intestine-derived CIC IBD networks were enriched for genes associated with known Crohn's disease and ulcerative colitis susceptibility loci contained within celltype-specific epigenetic regulatory regions.
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