Mapping the transcriptomics landscape of post-traumatic stress disorder symptom dimensions in World Trade Center responders

Gene expression has provided promising insights into the pathophysiology of posttraumatic stress disorder (PTSD), but specific regulatory transcriptomic mechanisms remain unknown. The current study addressed this limitation by analyzing transcriptome-wide RNA-Seq of whole blood samples from N=226 World Trade Center responders. The investigation focused on differential expression (DE) at gene, isoform, and alternative splicing (AS) levels associated with Posttraumatic Stress Disorder symptoms: total burden and its re-experiencing, avoidance, numbing, and hyperarousal subdimensions; and is the first study to characterize the AS landscape in PTSD. These dimensions were associated with 76, 1, 48, 15, and 49 genes, respectively (FDR<0.05). Similarly, they were associated with 103, 11, 0, 43, and 32 AS events. Avoidance differed the most from other dimensions with regard to DE genes, isoforms and AS correlates. Gene set enrichment analysis (GSEA) identified pathways involved in inflammatory and metabolic processes, which may have implications for the treatment of PTSD. Overall, findings shed a novel light on the wide range of transcriptomic alterations associated with PTSD at gene and AS levels. The DE analysis associated with PTSD subdimensions highlights the importance of studying PTSD symptom heterogeneity. Gene expression profiling of 226 samples using RNAseq; All are male volunteers and caucasian. The variable of interest in this study is PCL-17 (Posttraumatic Stress Disorder Checklist), which is a PTSD questionnaire score and is provided in the sample characteristics field.