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Gene expression associated with PTSD in World Trade Center responders: An RNA sequencing study

ABSTRACT: The gene expression approach has provided promising insights into the pathophysiology of PTSD. However, few studies used hypothesis-free transcriptome-wide expression approach. Transcriptome-wide expression study using RNA sequencing (RNA-Seq) of whole blood was conducted in 324 World Trade Center responders (201 with never, 81 current and 42 past PTSD). The current and never PTSD samples were randomly split to form both discovery (N=195) and replication (N=87) cohorts. Differentially expressed genes identified in RNA-Seq 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, and 5 (FKBP5, NDUFA1, CCDC85B, SNORD54, SNORD46) showed >1.2-fold difference in expression consistently between the discovery and replication cohorts. Several enriched biological pathways were found, including glucocorticoid receptor signaling and immunity-related pathways, but were not significant following FDR correction. The gene expression score achieved sensitivity of 0.917 and specificity of 0.508 for identifying PTSD cases in the replication cohort. It was similar in current and past PTSD, with both groups scoring higher than trauma-exposed controls. We confirmed the role of FKBP5 in PTSD and identified four additional differentially expressed genes that may constitute biomarkers for this condition. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97356 | GEO | 2018/02/13

REPOSITORIES: GEO

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Project description:While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14). In all 129 individuals, 1627 transcripts showed a significant correlation with plasma cortisol concentrations, suggesting their GR responsiveness. The correlation of 76 of these transcripts with cortisol plasma levels showed significant differences when stratifying by FKBP5 genotype in individuals with child abuse (Fisher z score ≥ 1.96) For these 76 transcripts, the mean absolute correlation coefficient with plasma cortisol was R = 0.23 in the risk allele carriers with child abuse, that is those exhibiting a demethylation of FKBP5 intron 7 as compared to R = 0.74 in the carriers of the protective genotype with child abuse where intron 7 methylation remains largely stable. This indicates a relative GR-resistance in the trauma exposed FKBP5 risk allele vs. protective genotype carriers. These 76 transcripts did not show a genotype-dependent difference in correlation coefficients in non-trauma exposed individuals suggesting that exposure to early trauma enhances FKBP5 genotype-dependent effect of GR sensitivity, most likely by epigenetic mechanisms. These findings suggest that the combination of FKBP5 risk allele carrier status and early trauma exposure alters the stress hormone-dependent regulation of several genes in peripheral blood cells, and might thereby enhance the reported association of early trauma with immune and inflammatory dysregulation, further promoting system-wide symptoms of stress-related disorders.

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Gene expression associated with PTSD in World Trade Center responders: An RNA sequencing study

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