ReviewPosttraumatic Stress Disorder Brain Transcriptomics: Convergent Genomic Signatures Across Biological Sex
Section snippets
PTSD Target Gene Prioritization and Mechanisms Underlying Sex-Specific GWAS Loci
A number of reports indicate differences in heritability between males and females with PTSD. The heritability estimated from twin studies ranges from 24% to 72% (9,11,35), with the heritability in females being 2 to 3 times higher than that in males (35). A summary of the most recent Psychiatric Genomics Consortium (PGC) and Million Veteran Program (MVP) GWASs for PTSD is presented in Table 1. The first iteration of the PGC PTSD Working Group (Freeze 1) included approximately 20,000
Sex-Specific Transcriptomic Insights of PTSD From Peripheral Blood
Most studies attempting to identify biomarkers of PTSD have focused on gene expression changes in the blood of patients with PTSD. Transcriptome-wide screens of peripheral blood have consistently identified dysregulation of immune and HPA function at onset and during development of PTSD. These studies have largely identified proinflammatory cytokines and glucocorticoid activity as underlying molecular correlates of PTSD (47). PTSD development has been characterized by increases in C-reactive
Sex-Specific Transcriptional Differences in PTSD Postmortem Brain
Recent efforts by the VA National Center for PTSD Brain Bank have given rise to a large, well-characterized collection of PTSD brains—the first of its kind (50). A recent multiregional transcriptomic study of PTSD postmortem brains identified numerous transcriptomic changes occurring in PFC (43). This study used a novel strategy of including a non-PTSD psychiatric control, MDD, in its design. This well-powered transcriptomic study included 143 donors and was balanced for sex (64 females and 79
Cell Type Transcriptional and Proportion Differences
Cell type marker enrichment in PTSD-associated gene co-expression modules highlights cell type–specific changes in gene expression and suggests potential changes in the cellular makeup of the frontal cortex in subjects with PTSD. Studies on human and rodent brain samples have reported alterations in specific cell types between sexes in response to stress disorders. For example, expression levels of the interneuron cell type marker SST and its related pathways were found to be decreased in
Sex-Specific Molecular Signatures Between PTSD and Other Traits
Recent studies have identified differences in molecular signatures based on sex in postmortem brains of subjects with MDD. A recent large postmortem study of 6 brain regions showed little transcriptional overlap between males and females with MDD (59). Further, co-expression analysis revealed downregulated DUSP6 transcript as a key driver in a female-specific module associated with MDD. Remarkably, knockdown of Dusp6 in a mouse model of depression, chronic variable stress, mimicked stress
Conclusions
There are now several well-powered GWASs that have identified many significant loci for PTSD risk. There are also currently several PTSD postmortem brain single-target transcriptomic studies and a single large multiregion whole-genome transcriptomic study. These data identify numerous biological mechanisms that may be associated with PTSD, but several distinct patterns begin to emerge from the overlap of the genetic and transcriptomic data. The first pattern is the stress response. CRHR1
Acknowledgments and Disclosures
This work was supported by the Department of Veterans Affairs, Veterans Health Administration, VISN 1 Career Development Award (to MJG) and Brain and Behavior Research Foundation Young Investigator Award (to MJG). The views expressed here are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government.
The data used for the analyses described in this article were obtained from Girgenti et al. (43).
The authors report no
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