A Functional Genomics Predictive Network Model Identifies Regulators of Inflammatory Bowel Disease

Nat Genet. 2017 Oct;49(10):1437-1449. doi: 10.1038/ng.3947. Epub 2017 Sep 11.

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.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Causality
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / genetics
  • Datasets as Topic
  • Disease Models, Animal
  • Female
  • Gene Knockdown Techniques
  • Gene Regulatory Networks*
  • Genes, Regulator*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genomics / methods*
  • Humans
  • Inflammatory Bowel Diseases / genetics*
  • Intestinal Mucosa / metabolism
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Genetic*
  • RNA, Small Interfering / genetics
  • T-Lymphocyte Subsets / transplantation
  • Transcriptome

Substances

  • RNA, Small Interfering