Genetic risk mechanisms of posttraumatic stress disorder in the human brain

Rahul A. Bharadwaj, Andrew E. Jaffe, Qiang Chen, Amy Deep-Soboslay, Aaron L. Goldman, Michelle I. Mighdoll, John A. Cotoia, Anna C. Brandtjen, Joo Heon Shin, Thomas M. Hyde, Venkata S. Mattay, Daniel R. Weinberger, Joel E. Kleinman

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Posttraumatic stress disorder (PTSD) follows exposure to a traumatic event in susceptible individuals. Recently, genome-wide association studies have identified a number of genetic sequence variants that are associated with the risk of developing PTSD. To follow up on identifying the molecular mechanisms of these risk variants, we performed genotype to RNA sequencing–derived quantitative expression (whole gene, exon, and exon junction levels) analysis in the dorsolateral prefrontal cortex (DLPFC) of normal postmortem human brains. We further investigated genotype–gene expression associations within the amygdala in a smaller independent RNA sequencing (Genotype-Tissue Expression [GTEx]) dataset. Our DLPFC analyses identified significant expression quantitative trait loci (eQTL) associations for a “candidate” PTSD risk SNP rs363276 and the expression of two genes: SLC18A2 and PDZD8, where the PTSD risk/minor allele T was associated with significantly lower levels of gene expression for both genes, in the DLPFC. These eQTL associations were independently confirmed in the amygdala from the GTEx database. Rs363276 “T” carriers also showed significantly increased activity in the amygdala during an emotional face-matching task in healthy volunteers. Taken together, our preliminary findings in normal human brains represent a tractable approach to identify mechanisms by which genetic variants potentially increase an individual's risk for developing PTSD.

Original languageEnglish (US)
Pages (from-to)21-30
Number of pages10
JournalJournal of neuroscience research
Volume96
Issue number1
DOIs
StatePublished - Jan 2018

Keywords

  • amygdala
  • dorsolateral prefrontal cortex (DLPFC)
  • expression quantitative trait loci (eQTL)
  • face-matching task (FMT)
  • functional magnetic resonance imaging (fMRI)
  • methylation quantitative trait loci (meQTL)
  • postmortem human brain
  • posttraumatic stress disorder (PTSD)

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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