Identification of key genes involved in post-traumatic stress disorder: Evidence from bioinformatics analysis

Abstract

Background: Post-traumatic stress disorder (PTSD) is a serious stress-related disorder.

Aim: To identify the key genes and pathways to uncover the potential mechanisms of PTSD using bioinformatics methods.

Methods: Gene expression profiles were obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified by using GEO2R. Gene functional annotation and pathway enrichment were then conducted. The gene-pathway network was constructed with Cytoscape software. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was applied for validation, and text mining by Coremine Medical was used to confirm the connections among genes and pathways.

Results: We identified 973 DEGs including 358 upregulated genes and 615 downregulated genes in PTSD. A group of centrality hub genes and significantly enriched pathways (MAPK, Ras, and ErbB signaling pathways) were identified by using gene functional assignment and enrichment analyses. Six genes (KRAS, EGFR, NFKB1, FGF12, PRKCA, and RAF1) were selected to validate using qRT-PCR. The results of text mining further confirmed the correlation among hub genes and the enriched pathways. It indicated that these altered genes displayed functional roles in PTSD via these pathways, which might serve as key signatures in the pathogenesis of PTSD.

Conclusion: The current study identified a panel of candidate genes and important pathways, which might help us deepen our understanding of the underlying mechanism of PTSD at the molecular level. However, further studies are warranted to discover the critical regulatory mechanism of these genes via relevant pathways in PTSD.

Keywords: Bioinformatics analysis; Differentially expressed genes; Gene-pathway co-expression; Key pathway; Microarray; Post-traumatic stress disorder.

Figure 1

Venny diagrams of differentially expressed genes at the time point of 24 h post 10 d compared with 42 d post 10 d after aggressor exposure sessions. A: Overlapping upregulated differentially expressed genes; B: Overlapping downregulated differentially expressed genes.

Figure 2

Gene ontology annotation and pathway enrichment of differentially expressed genes associated with post-traumatic stress disorder. A: Gene ontology analysis of differentially expressed genes (top 20); B: The Kyoto Encyclopedia of Genes and Genomes enrichment analysis of differentially expressed genes (top 20) with enriched score values setting as –log10 (P values). GO: Gene ontology.

Figure 3

Co-expression pattern of the most significantly enriched pathways of differentially expressed genes involved in post-traumatic stress disorder. In the graphic, red cycles as the upregulated genes, green cycles as the downregulated genes, and blue cycles as the signaling pathway.

Figure 4

The mRNA expression of hub genes in control and aggressed-exposed groups. The results are shown as the mean ± SD, ^aP < 0.05. Agg-E: Aggressed-exposed; KRAS: KRAS proto-oncogene, GTPase; EGFR: Epidermal growth factor receptor; NFKB1: Nuclear factor kappa B subunit 1; FGF12: Fibroblast growth factor 12; PRKCA: Protein kinase C alpha; RAF1: Raf-1 proto-oncogene, serine/threonine kinase.

Figure 5

Linear association among the hub genes and co-expressed pathways using Coremine Medical online tool. The thicker the line, the closer the relationship. KRAS: KRAS proto-oncogene, GTPase; EGFR: Epidermal growth factor receptor; NFKB1: Nuclear factor kappa B subunit 1; FGF12: Fibroblast growth factor 12; PRKCA: Protein kinase C alpha; RAF1: Raf-1 proto-oncogene, serine/threonine kinase.

Figure 6

The immobility time in forced swim test and tail suspension test, and the path length of open-field test. Data are presented as the mean ± SD, ^aP < 0.05. Agg-E: Aggressed-exposed; FST: Forced swim test; TST: Tail suspension test; OFT: Open-field test.