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

• DOI: 10.1016/j.celrep.2020.107716
• Publication Date: 2020-06-02T14:37:50Z
• Authors: Laura M. Huckins; Chris Chatzinakos; Michael S. Breen; Jakob Hartmann; Torsten Klengel; Ana C. da Silva A...; Amanda Dobbyn; Kiran Girdhar; Gabriel E. Hoffman; Claudia Klengel; Mark W. Logue; Adriana Lori; Adam X. Maihofer; Filomene G. Morrison; Hoang T. Nguyen; Yongjin Park; Douglas Ruderfer; Laura G. Sloofman; Sanne J.H. van Rooij; Dewleen G. Baker; Chia-Yen Chen; Nancy Cox; Laramie E. Duncan; Mark A. Geyer; Stephen J. Glatt; Hae Kyung Im; Victoria B. Risbr...; Jordan W. Smoller; Dan J. Stein; Rachel Yehuda; Israel Liberzon; Karestan C. Koenen; Tanja Jovanovic; Manolis Kellis; Mark W. Miller; Silviu-Alin Bacanu; Caroline M. Nieve...; Joseph D. Buxbaum; Pamela Sklar; Kerry J. Ressler; Eli A. Stahl; Nikolaos P. Daska...
• Keywords: FKBP5

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