Gene expression differences in PTSD are uniquely related to the intrusion symptom cluster: A transcriptome-wide analysis in military service members

•Gene expression differences were almost entirely attributed to intrusion symptoms.•No gene expression differences were attributed to the other PTSD symptom clusters.•PTSD-like symptoms due to comorbid conditions may be represented by different genes.•Immune systems were upregulated in PTSD and downregulated with symptom reduction. Posttraumatic stress disorder (PTSD) is associated with wide-spread immune dysregulation; however, little is known about the gene expression differences attributed to each PTSD symptom cluster. This is an important consideration when identifying diagnostic and treatment response markers in highly comorbid populations with mental and physical health conditions that share symptoms. To this aim, we utilized a transcriptome-wide analysis of differential gene expression in peripheral blood by comparing military service members: (1) with vs. without PTSD, (2) with high vs. low PTSD cluster symptom severity, and (3) with improved vs. not improved PTSD symptoms following 4–8 weeks of evidenced-based sleep treatment. Data were analyzed at a ±2.0-fold change magnitude with subsequent gene ontology-based pathway analysis. In participants with PTSD (n = 39), 89 differentially expressed genes were identified, and 94% were upregulated. In participants with high intrusion symptoms (n = 22), 1040 differentially expressed genes were identified, and 98% were upregulated. No differentially expressed genes were identified for the remaining two PTSD symptom clusters. Ten genes (C5orf24, RBAK, CREBZF, CD69, PMAIP1, AGL, ZNF644, ANKRD13C, ESCO1, and ZCCHC10) were upregulated in participants with PTSD and high intrusion symptoms at baseline and downregulated in participants with improved PTSD symptoms following treatment. Pathway analysis identified upregulated immune response systems and metabolic networks with a NF-kB hub, which were downregulated with symptom reduction. Molecular biomarkers implicated in intrusion symptoms and PTSD symptom improvement may inform the development of therapeutic targets for precise treatment of PTSD.