Table 5.
Description of IBS-associated modules
| Module (size) | Description |
|---|---|
| Neuroactive ligand receptors 1 (758) | Hub genes enriched (0.01) for KEGG pathway “Neuroactive ligand-receptor interaction” and include 5-hydroxytryptamine receptor 4 (HTR4), cholinergic receptor muscarinic 1 (CHRM1), dopamine receptor D4 (DRD4), and glutamate metabotropic receptor 2 (GRM2). Full module also enriched for GO-BP “negative regulation of cytokine production” (0.002), and “negative regulation of tumor necrosis factor production” (0.0005) |
| Differentiation (435) | Hub genes enriched (FDR <0.05) for cell differentiation and nervous system development. Representative genes for the latter included glial cell derived neurotrophic factor (GDNF) and beta tubulin (TUBB2B). The module overall was enriched for RNA transcription (0.005). |
| Ion transmembrane transport (248) | Enriched for GO:BP “regulation of transmembrane ion transport” (0.005) |
| Cell cycle (273) | Very heavily enriched for cell-cycle genes (GO:BP, FDR = 1.5e-49) |
| Translation (2685) | Highly enriched for terms related to protein translation. Top two are GO:BP “RNA splicing via transesterification reactions” and “ribonucleoprotein complex biogenesis” (1.8e-07 for each) |
| Mitochondrial (1915) | Module and hub genes heavily enriched for terms and pathways related to cellular respiration and oxidative phosphorylation (FDR <1e-15 for several) |
| Hydrolase activity (165) | No terms or pathways enriched P < 0.005 or FDR <0.05. Nine of 45 hub genes map to GO:BP “regulation of hydrolase activity” (0.02) |
| cAMP/PKA (184) | Based on Ingenuity Pathway Analysis. |
| Development (234) | Hub genes marginally (0.006) enriched for “anatomical structure development” and “single organism developmental process.” Relevant genes include the transcriptional regulators GATA binding protein 2 (GATA2), Sp3 transcription factor (SP3) and homeobox B3 (HOXB3). |
| IgA production (127) | Heavily enriched for GO terms related to adaptive immune response (<0.005) as well as KEGG pathway “Intestinal immune network for IgA production” (FDR <0.0005). Hub genes include three HLA class molecules (DMA, DRA, DMB) integrin subunit alpha and beta (ITGA4, ITGB7). |
| Actin (77) | Enriched (<0.005) for several terms related to regulation of actin polymerization. |
| Cell junction (889) | Enriched (FDR <0.05) for GO:MF “cadherin-binding in cell adhesion” and CC “adherens junction.” Relevant genes include vinculin (VCL), tight junction protein 1 (TJP1) and catenin delta 1 (CTNND1) |
| GEF activity (224) | Hub genes enriched for GO:BP “guanyl-nucleotide exchange factor activity” (<0.005). |
| Transcription (143) | GO:BP “DNA-templated transcription” is most representative (19 genes, 0.04) |
| DNA repair (168) | Enriched for several terms related to DNA repair (i.e., GO:BP “double-strand break repair via nonhomologous end joining”, 0.001) |
| Neuronal (578) | GO:BP: “protein localization to synapse” is most enriched (0.0001) and there are 25 genes mapping to GO:BP “nervous system development” (0.03). Relevant genes include neuronal cell adhesion molecule (NRCAM) and neuropeptide Y (NPY). |
| Neuroimmune (1074) | Hub genes are enriched for sensory perception (FDR <0.05) and include 6 olfactory receptors. Hub genes also contain multiple genes related to the inflammatory response and innate immune system. These include tumor necrosis factor (TNF), CD70, CD80, macrophage expressed 1/Perforin-2 (MPEG1), toll like receptor 9 (TLR9), mucin 22 (MUC22), defensin beta 113 (DEFB113), cysteine rich secretory protein 3 (CRISP3), and the serine protease inhibitors serpin family E members 1&2 (SERPINE1/2). |
| Apoptosis (275) | Enriched for GO:BP “positive regulation of apoptotic process” (<0.005). Relevant genes include caspase 2 (CASP2) and slit guidance ligand 2 (SLIT2). |
| Negative regulation of JAK/STAT (139) | The top GO:BP term is “negative regulation of JAK-STAT cascade (0.003) based on caveolin 1 (CAV1) and inositol polyphosphate-5-phosphatase F (INPP5F). |
| GFRA4 (161) | No significantly enriched terms or pathways. GDNF family receptor alpha is one of top genes (MM = 0.93). Nonsignificantly enriched terms include GO:BP “regulation of GTPase activity” (0.05), “cellular response to BMP stimulus” (0.02), “glial cell-derived neurotrophic factor receptor signaling pathway” (0.04), and “catechol-containing compound metabolic process” (0.01). |
| Endothelial (107) | Enriched (0.001) for GO:BP “regulation of tube size” based on expression of endothelial nitric oxide synthase (eNOS, NOS3) and adrenoceptor alpha 1A (ADRA1A). |
| Neuroactive ligand receptors 2 (892) | Hub genes enriched for membrane proteins (GO:CC, FDR <0.05). Top 100 genes include receptors for NPY (NPY1R) and neuropeptides B and W (NPBWR1), melanocortin (MC5R) and GABA (GABRG1). |
| SSPO (186) | SCO-Spondin (SSPO) is among top two genes in module (MM = 0.95). GO:BP “ion transport” is also enriched (<0.005) |
| GPCRs (328) | Enriched (<0.005) for GO:BP “G-protein coupled receptor signaling pathway”. Relevant genes include 5-hydroxytryptamine receptors 6 and 3D(HTR6, HTR3D), urocortin 2 (UCN2), and four olfactory receptors. |
| Keratins (827) | Hub genes enriched for GO:CC “Intermediate filament cytoskeleton” (FDR = 0.05). The majority of these are keratins or keratin associated proteins. The module overall (but not hub genes exclusively) is enriched for GO:BP “response to steroid hormone” (0.009). Relevant genes include hepatocyte nuclear factor 4 alpha (HNF4A), KRAS proto-oncogene, GTPase (KRAS) and estrogen related receptor alpha (ESRRA). |
| OPRM1 (198) | Not significantly enriched for pathways or terms. Opioid receptor mu 1 (OPRM1) is a hub gene (MM = 0.84). Marginally enriched for GO:BP “sensory response to pain” (P = 0.02) due to OPRM1 and purinergic receptor P2X 4 (P2RX4). |
Module membership (MM) is the correlation with module eigengene. Hub genes are those with MM > 0.8. MM P values < 1e-7 for all hub genes. Overrepresented terms were determined using the hypergeometric function in the GOstats package for R(44) or DAVID. (55, 56). Numbers in parentheses are unadjusted P values except where noted. GO, gene ontology; BP, biological process; MF, molecular function; CC, cellular component; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; GEF, guanine nucleotide exchange factor; GPCRs, G-protein coupled receptors.