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. Author manuscript; available in PMC: 2018 Oct 1.
Published in final edited form as: Nat Genet. 2017 Sep 11;49(10):1437–1449. doi: 10.1038/ng.3947

Figure 1.

Figure 1

An integrative approach for constructing a predictive network model of IBD, and identifying and validating master regulators of these networks. (a) Identification of causal IBD genes. We identified IBD-associated DNA variants in immune cells and digestive-tissue-derived CRE regions, some of which also corresponded to eQTLs derived from patients with IBD. Identification of a core IAM. Three different populations representing distinct states of disease were profiled, and the resulting data were integrated to build predictive molecular networks of the intestine. The core IAM was derived from coexpression modules from pediatric and adult patients with moderate and advanced IBD who were screened to link the immune network to active IBD in a disease-relevant context. The core IAM from all three populations was identified as the most highly enriched for genes in the immune network but then also highly enriched for causal IBD GWAS genes and macrophage expression. (b) Identification and annotation of IBD networks. Subnetworks for each IBD cohort representing the core IAM were identified as different instances of the CIC IBD network model and annotated using a diverse set of data. Identification and ranking of KDGs. KDGs were identified from the CIC IBD networks and prioritized by the size of their effect on the network as well as the degree of disease subnetwork support. (c) KDG experimental validation. To validate the utility of the CIC IBD model as a regulatory framework for modeling IBD, the top KDGs were experimentally validated in IBD mouse models and human macrophage cell systems. (d) Molecular validation of the CIC IBD model. Signatures from mouse intestine and human macrophages were projected onto the CIC IBD model to evaluate the degree to which the model predicted KDG perturbation signatures. (e) Phenotype validations. In vitro and in vivo phenotypes of inflammation were measured to evaluate the functional role of the KDGs in the context of IBD. CD, Crohn's disease; UC, ulcerative colitis; KD, knockdown.