Elsevier

Biological Psychiatry

Volume 91, Issue 1, 1 January 2022, Pages 6-13
Biological Psychiatry

Review
Posttraumatic Stress Disorder Brain Transcriptomics: Convergent Genomic Signatures Across Biological Sex

https://doi.org/10.1016/j.biopsych.2021.02.012Get rights and content

Abstract

While a definitive understanding of the molecular pathology of posttraumatic stress disorder (PTSD) is far from a current reality, it has become increasingly clear that many of the molecular effects of PTSD are sex specific. Women are twice as likely as men to develop PTSD after a traumatic event, and neurobiological evidence suggests that there are structural differences between the brains of males versus females with PTSD. Recent advances in genomic technologies have begun to shed light on the sex-specific molecular determinants of PTSD, which seem to be governed predominantly by dysfunction of GABAergic (gamma-aminobutyric acidergic) signaling and immune function. We review the current state of the field of PTSD genomics focusing on the effect of sex. We provide an overview of difference in heritability of PTSD based on sex, how difference in gene regulation based on sex impacts the PTSD brain, and what is known about genomic regulation that is dysregulated in specific cell types in PTSD.

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

References (72)

  • L.M. Huckins et al.

    Analysis of genetically regulated gene expression identifies a prefrontal PTSD gene, SNRNP35, specific to military cohorts

    Cell Rep

    (2020)
  • I.C. Passos et al.

    Inflammatory markers in post-traumatic stress disorder: A systematic review, meta-analysis, and meta-regression

    Lancet Psychiatry

    (2015)
  • T.C. Neylan et al.

    Suppressed monocyte gene expression profile in men versus women with PTSD

    Brain Behav Immunity

    (2011)
  • G.S. Kim et al.

    Neuroepigenetics of post-traumatic stress disorder

    Prog Mol Biol Transl

    (2018)
  • M.L. Seney et al.

    Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression

    Neurobiol Dis

    (2015)
  • M.L. Seney et al.

    Opposite molecular signatures of depression in men and women

    Biol Psychiatry

    (2018)
  • C. Sheth et al.

    Reduced gamma-amino butyric acid (GABA) and glutamine in the anterior cingulate cortex (ACC) of veterans exposed to trauma

    J Affect Disorders

    (2019)
  • N. Breslau

    The epidemiology of posttraumatic stress disorder: What is the extent of the problem?

    J Clin Psychiatry

    (2001)
  • E. Bromet et al.

    Risk factors for DSM-III-R posttraumatic stress disorder: Findings from the National Comorbidity Survey

    Am J Epidemiol

    (1998)
  • T. Jovanovic et al.

    How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD

    Am J Psychiatry

    (2010)
  • T. Jovanovic et al.

    Impaired fear inhibition is a biomarker of PTSD but not depression

    Depress Anxiety

    (2010)
  • T.A. Mellman et al.

    Predictors of post-traumatic stress disorder following severe injury

    Depress Anxiety

    (2001)
  • W.R. True et al.

    A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms

    Arch Gen Psychiatry

    (1993)
  • M.B. Stein et al.

    Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: A twin study

    Am J Psychiatry

    (2002)
  • K.C. Koenen et al.

    A high risk twin study of combat-related PTSD comorbidity

    Twin Res

    (2003)
  • K.C. Koenen et al.

    A twin registry study of the relationship between posttraumatic stress disorder and nicotine dependence in men

    Arch Gen Psychiatry

    (2005)
  • J. Gelernter et al.

    Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans

    Nat Neurosci

    (2019)
  • R.C. Kessler et al.

    Posttraumatic stress disorder in the National Comorbidity Survey

    Arch Gen Psychiatry

    (1995)
  • R.C. Kessler et al.

    The global burden of mental disorders: An update from the WHO World Mental Health (WMH) Surveys

    Epidemiol Psichiatr Soc

    (2009)
  • N. Breslau et al.

    Trauma and posttraumatic stress disorder in the community

    Arch Gen Psychiatry

    (1998)
  • T.L. Holbrook et al.

    Gender differences in long-term posttraumatic stress disorder outcomes after major trauma: Women are at higher risk of adverse outcomes than men

    J Trauma

    (2002)
  • S. Seedat et al.

    Post-traumatic stress disorder in women: Epidemiological and treatment issues

    CNS Drugs

    (2005)
  • S.E. Baran et al.

    Prefrontal cortex lesions and sex differences in fear extinction and perseveration

    Learn Mem

    (2010)
  • J.M. Goldstein et al.

    Sex differences in stress response circuitry activation dependent on female hormonal cycle

    J Neurosci

    (2010)
  • L. Kogler et al.

    Sex differences in cognitive regulation of psychosocial achievement stress: Brain and behavior

    Hum Brain Mapp

    (2014)
  • E. Brivio et al.

    Sex differences: Transcriptional signatures of stress exposure in male and female brains

    Genes Brain Behav

    (2020)
  • View full text