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

• Published in: Nature neuroscience Vol. 24; no. 1; pp. 24 - 33
• Main Authors: Girgenti, Matthew J., Wang, Jiawei, Ji, Dingjue, Cruz, Dianne A., Stein, Murray B., Gelernter, Joel, Young, Keith A., Huber, Bertrand R., Williamson, Douglas E., Friedman, Matthew J., Krystal, John H., Zhao, Hongyu, Duman, Ronald S.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-01-2021; Nature Publishing Group
• Subjects: 38/91; 631/208/199; 631/378/1689/1830; Adult; Animal Genetics and Genomics; Autopsy; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain architecture; Brain Chemistry - genetics; Brain research; Cohort Studies; Correlation analysis; Depressive Disorder, Major - genetics; Female; Gene expression; Gene Expression Regulation - genetics; Gene Regulatory Networks; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic transcription; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotypes; Humans; Interneurons - metabolism; Liability; Male; Mental depression; Mental disorders; Methods; Middle Aged; Nerve Tissue Proteins - genetics; Neurobiology; Neurosciences; Physiological aspects; Post traumatic stress disorder; Prefrontal cortex; Psychological stress; Sex Characteristics; Sexual dimorphism; Stress Disorders, Post-Traumatic - genetics; Stress Disorders, Post-Traumatic - physiopathology; Transcriptome; Traumatic brain injury; Young Adult; United States
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-020-00748-7

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.
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.