Transcriptomic organization of the human brain in post-traumatic stress disorder

A transcriptome-wide characterization of the molecular pathology of post-traumatic stress disorder (PTSD) postmortem brains provides a comprehensive resource for mechanistic insight and therapeutic development. Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.

Automated summary

This study provides comprehensive insights into the molecular pathology of post-traumatic stress disorder (PTSD) through transcriptome analysis of postmortem brains, revealing extensive remodeling of gene expression networks and identifying genetic susceptibility factors, as well as marked transcriptional sexual dimorphism. Additionally, comparison with major depressive disorder cohorts shows significant differences between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity, supporting the notion that PTSD has distinct molecular determinants.