Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts

Cell Rep. 2020 Jun 2;31(9):107716. doi: 10.1016/j.celrep.2020.107716.

Abstract

To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.

Keywords: GWAS; PTSD; blood; civilian; glucocorticoid; military; prefrontal cortex; sex; splicing; transcriptomic imputation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Case-Control Studies
  • Cohort Studies
  • Dexamethasone / pharmacology
  • Down-Regulation / drug effects
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease
  • Humans
  • Leukocytes / cytology
  • Leukocytes / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Military Personnel
  • Prefrontal Cortex / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / blood
  • Repressor Proteins / metabolism
  • Ribonucleoproteins, Small Nuclear / antagonists & inhibitors
  • Ribonucleoproteins, Small Nuclear / genetics*
  • Ribonucleoproteins, Small Nuclear / metabolism
  • Stress Disorders, Post-Traumatic / blood
  • Stress Disorders, Post-Traumatic / diagnosis
  • Stress Disorders, Post-Traumatic / genetics*

Substances

  • RNA, Small Interfering
  • Repressor Proteins
  • Ribonucleoproteins, Small Nuclear
  • SNRNP35 protein, human
  • ZNF140 protein, human
  • Dexamethasone