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

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.
Competing Interests: Declaration of Interests J.W.S. is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. D.J.S. has received research grants and/or consultancy honoraria from Biocodex, Lundbeck, and Sun. R.Y. is a co-inventor of the following patent: “Genes associated with posttraumatic-stress disorder, WO 2010029176 A1.” I.L. has been a consultant for ARMGO Pharmaceuticals, Sunovion Pharmaceuticals, and Trimaran Pharma. K.J.R. has received consulting income from Alkermes and is on scientific advisory boards for Janssen, Verily, and Resilience Therapeutics. He has also received sponsored research support from Takeda and Brainsway. N.P.D. has held a part-time paid position at Cohen Veteran Bioscience. He has also been a consultant for Sunovion Pharmaceuticals.
(Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)