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Transcriptomic Organization of Human Posttraumatic Stress Disorder

By Matthew J. Girgenti, Jiawei Wang, Dingjue Ji, Dianne Cruz, Traumatic Stress Brain Research Study Group, the Million Veteran Program, Murray B Stein, Joel Gelernter, Keith Young, Bertrand R. Huber, Douglas E. Williamson, Matthew J. Friedman, John H Krystal, Hongyu Zhao, Ronald S. Duman

Posted 28 Jan 2020
bioRxiv DOI: 10.1101/2020.01.27.921403 (published DOI: 10.1016/j.biopsych.2020.02.330)

Posttraumatic stress disorder (PTSD) affects approximately 8% of the general population, with higher rates in extreme stress groups, including combat veterans or victims of sexual assault. Despite extensive study of the neurobiological correlates of PTSD, little is known about its molecular substrates. Here differential gene expression and network analyses of 4 prefrontal cortex (PFC) postmortem subregions of male and female PTSD subjects demonstrates extensive remodeling of the transcriptomic landscape. The data revealed a highly connected down-regulated set of interneuron transcripts in the most significant gene network associated with PTSD and integration of this data with genotype data from the largest PTSD GWAS identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked sexual dimorphism in the transcriptomic signatures that could contribute to the higher rates of PTSD in women. Comparison with a matched major depressive disorder (MDD) cohort revealed significant divergence between the molecular profiles of subjects with PTSD and depression despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the PFC that contribute to the pathophysiology of PTSD in humans.

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