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Abstract
The gene expression approach has provided promising insights into the pathophysiology of posttraumatic stress disorder (PTSD). However, few studies used hypothesis-free transcriptome-wide approach to comprehensively understand gene expression underpinning PTSD. A transcriptome-wide expression study using RNA sequencing of whole blood was conducted in 324 World Trade Center responders (201 with never, 81 current, 42 past PTSD). Samples from current and never PTSD reponders were randomly split to form discovery (N = 195) and replication (N = 87) cohorts. Differentially expressed genes were used in pathway analysis and to create a polygenic expression score. There were 448 differentially expressed genes in the discovery cohort, of which 99 remained significant in the replication cohort, including FKBP5, which was found to be up-regulated in current PTSD regardless of the genotypes. Several enriched biological pathways were found, including glucocorticoid receptor signaling and immunity-related pathways, but these pathways did not survive FDR correction. The polygenic expression score computed by aggregating 30 differentially expressed genes using the elastic net algorithm achieved sensitivity/specificity of 0.917/0.508, respectively for identifying current PTSD in the replication cohort. Polygenic scores were similar in current and past PTSD, with both groups scoring higher than trauma-exposed controls without any history of PTSD. Together with the pathway analysis results, these findings point to HPA-axis and immune dysregulation as key biological processes underpinning PTSD. A novel polygenic expression aggregate that differentiates PTSD patients from trauma-exposed controls might be a useful screening tool for research and clinical practice, if replicated in other populations.
Highlights
Posttraumatic stress disorder (PTSD) is a persistent and debilitating condition that affects approximately 7% of the US population[1]
A handful of transcriptome-wide gene expression studies of PTSD have been published to date[13,17,18,19,20,21,22,23], most of which rely on small sample sizes (N ≤ 30)
We found 448 differentially expressed genes in the discovery cohort, out of which 99 remained significant in the replication cohort, and 5 had an estimated fold change magnitude > 1.2 and a consistent fold change estimates between discovery and replication cohorts, These 5 genes were FKBP5, NDUFA1, CCDC85B, SNORD54, and SNORD46
Summary
Posttraumatic stress disorder (PTSD) is a persistent and debilitating condition that affects approximately 7% of the US population[1]. Kuan et al Translational Psychiatry (2017)7:1297 expression underlying this disorder is the transcriptomewide design, which allows for a thorough investigation of the expression patterns without relying on a priori knowledge of genetic risk factors[16]. Mehta et al (2013) examined gene expression profiles of 169 trauma-exposed general population participants (61 with current PTSD) and found gene expression differences between PTSD cases and controls[13]. They found downstream biological pathways enriched by these genes in PTSD, including pathways involved in cellular processes (e.g., cell migration and adhesion) and immunity (e.g., T cell activation).
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