Cross-Species Convergence of Brain Transcriptomic and Epigenomic Findings in Posttraumatic Stress Disorder: A Systematic Review

Abstract

Introduction: Posttraumatic stress disorder (PTSD) is a complex multifactorial disorder influenced by the interaction of genetic and environmental factors. Analyses of epigenomic and transcriptomic modifications may help to dissect the biological factors underlying the gene-environment interplay in PTSD. To date, most human PTSD epigenetics studies have used peripheral tissue, and these findings have complex and poorly understood relationships to brain alterations. Studies examining brain tissue may help characterize the brain-specific transcriptomic and epigenomic profiles of PTSD. In this review, we compiled and integrated brain-specific molecular findings of PTSD from humans and animals.

Methods: A systematic literature search according to the PRISMA criteria was performed to identify transcriptomic and epigenomic studies of PTSD, focusing on brain tissue from human postmortem samples or animal-stress paradigms.

Results: Gene- and pathway-level convergence analyses revealed PTSD-dysregulated genes and biological pathways across brain regions and species. A total of 243 genes converged across species, with 17 of them significantly enriched for PTSD. Chemical synaptic transmission and signaling by G-protein-coupled receptors were consistently enriched across omics and species.

Discussion: Our findings point out dysregulated genes highly replicated across PTSD studies in humans and animal models and suggest a potential role for the corticotropin-releasing hormone/orexin pathway in PTSD's pathophysiology. Further, we highlight current knowledge gaps and limitations and recommend future directions to address them.

Keywords: Brain; Central nervous system; DNA methylation; Gene expression; Posttraumatic stress disorder.

Fig. 1.

Study overview. a Flow diagram of the PRISMA study selection workflow in our systematic literature review. The identification and screening process of selected reports, focused on brain-specific transcriptomic and epigenomic studies of PTSD in humans and animal models, is shown. b Cross-species convergence in PTSD. The number of identified transcriptomic and epigenomic studies in animal models and humans is depicted. A high variability is observed in the brain regions examined across species. Subgenual prefrontal cortex (sgPFC), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (dlPFC), dorsolateral anterior cingulate cortex (dACC), ventromedial prefrontal cortex (vmPFC), amygdala (AMY), hippocampus (Hippo), hemibrain (Hemibr), medial prefrontal cortex (mPFC), ventral striatum (VS), septal region (SE), corpus striatum (ST).

Fig. 2.

Pathway-level convergence. Heatmap showing biological pathways in which human and rodent datasets converge.

Fig. 3.

Protein-protein interaction (PPI) enrichment analysis. PPI analysis was performed using the Molecular Complex Detection (MCODE) algorithm implemented in Metascape. This PPI contains the subset of proteins that interact in common pathways colored by counts identified in each study.

Fig. 4.

Convergent PTSD genes across species. a This ideogram illustrates the 17 convergent genes identified in our cross-species analysis that were significantly enriched for PTSD. b Cleveland plot showing fold chance (FC) direction of the 17 convergent PTSD genes across species. c GO enrichment analysis for the 17 convergent PTSD genes across species.

Fig. 5.

A schematic diagram of the proposed model of convergent genes in PTSD. In this diagram, we show a proposed model of how identified convergent genes may interact in the context of PTSD. The orexin pathway may mediate CRH release in the hypothalamus, activating the CRH pathway. CRH binding to GPCRs may modulate downstream regulatory mechanisms including gene expression and chemical synaptic signaling.