Expression and methylation in posttraumatic stress disorder and resilience; evidence of a role for odorant receptors

Abstract

Post-traumatic stress disorder (PTSD) is a common and potentially disabling disorder that develops in 1/5 to 1/3 of people exposed to severe trauma. Twin studies indicate that genetic factors account for at least one third of the variance in the risk for developing PTSD, however, the specific role for genetic factors in the pathogenesis of PTSD is not well understood. We studied genome-wide gene expression and DNA methylation profiles in 12 participants with PTSD and 12 participants who were resilient to similar severity trauma exposure. Close to 4000 genes were differentially expressed with adjusted p<0.05, fold-change >2, with all but 3 upregulated with PTSD. Eight odorant/olfactory receptor related genes were up-regulated with PTSD as well as genes related to immune activation, the Gamma-Aminobutyric Acid A (GABAA) receptor, and vitamin D synthesis. No differences with adjusted significance for DNA methylation were found. We conclude that increased gene expression may play an important role in PTSD and this expression may not be a consequence of DNA methylation. The role of odorant receptor expression warrants independent replication.

Keywords: Biomarker; Epigenetic; GABAA receptor; Microarray; Odorant receptor; Vitamin D Synthesis.

Figure 1

Canonical and functional pathway analysis. A. Global canonical pathway analysis were performed using Ingenuity Pathway Knowledge Base to deduce the upregulation and downregulation of the cellular pathways. The dataset contains all the genes differentially expressed (p<0.05, fold change >2). The ratio is computed as the number of given genes in one canonical pathway divided by the total number of genes in that pathway. B. Global functional pathway analysis was conducted using Ingenuity Pathway Knowledge Base to extrapolate the cellular functions comparing cases and controls. In all the panels above, p value (p<0.05) indicating the statistical significance was calculated using the right-tailed Fischer’s exact test.

Figure 2

Hierarchical clustering of the top 103 genes (p<0.05, fold change > 2) generated from Ingenuity Pathway Knowledge Base. Hierarchical gene clustering showed significant changes in gene expression comparing PTSD cases and the resilient controls. Five major clusters of functional genes were created from the heat map. Complete gene list of each cluster along with its fold change and p value is given in Supplementary Table 1.

Figure 3

Gene networks generated from the selected 103 genes using Ingenuity Pathway Knowledge Base. A. Gene network centered at NF-κB, a transcription regulator that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. B. Gene network centered at TNF, a multifunctional proinflammatory cytokine.

Figure 3

Gene networks generated from the selected 103 genes using Ingenuity Pathway Knowledge Base. A. Gene network centered at NF-κB, a transcription regulator that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. B. Gene network centered at TNF, a multifunctional proinflammatory cytokine.

Figure 4

Figure 5