Figure 4.
Enrichment analysis of KDG subnetworks. (a) Predicted transcriptional signature of 5 KDGs in the adult IBD networks. (b) The KDG (diamond) GPSM3 subnetwork is 2.76-fold enriched (Fisher's exact test, P < 0.008) for monocyte and macrophage IBD CRESNPs (light green) and 3.58-fold enriched (Fisher's exact test, P < 1.89 × 10−9) for differentially expressed nodes in the Gpsm3 DSS knockout signature (forest green) or both (bright green). Nodes present in the CRP, calprotectin, and lactoferrin trait signatures (blue border) are represented. The GPSM3 subnetwork reflects genes involved in macrophage function. C1orf228 (encoding p40, the molecular target of ustekinumab) is also present in this subnetwork (red). (c) The KDG (diamond) DOCK2 subnetwork is 2.2-fold enriched (Fisher's exact test, P = 0.02) for T cell IBD CRESNPs (light green), 5.13-fold enriched in T cell expression (Fisher's exact test, P = 1.84 × 10−7), and 4.59-fold enriched for genes upregulated in the DOCK2 perturbation signature (Fisher's exact test, P = 7.91 × 10−18) (forest green) or both (bright green). The DOCK2 subnetwork contains many genes represented in the CRP, calprotectin, and lactoferrin trait signatures from the CERTIFI cohort (blue border). Also represented is the IL-12Rβ1 receptor chain (in red) that comprises a chain in the IL-12 and IL-23 receptor and binds p40, the ligand to ustekinumab. The DOCK2 subnetwork is also 2.2-fold enriched (Fisher's exact test, P = 0.005) in a ROR-γT knockout differential expression signature (triangle). Each circular node represents an expressed gene, and the directed edges connecting genes represent causal or correlative relationships among the genes in the populations from which the network was built.