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

Citation:
Cell Reports. 2020; Jun 2;31(9):107716. doi: 10.1016/j.celrep.2020.107716.
Authored By:
Huckins LM, Chatzinakos C, Breen MS, Hartmann J, Klengel T, da Silva Almeida AC, Dobbyn A, Girdhar K, Hoffman GE, Klengel C, Logue MW, Lori A, Maihofer AX, Morrison FG, Nguyen HT, Park Y, Ruderfer D, Sloofman LG, van Rooij SJH; PTSD Working Group of Psychiatric Genomics Consortium, Baker DG, Chen CY, Cox N, Duncan LE, Geyer MA, Glatt SJ, Im HK, Risbrough VB, Smoller JW, Stein DJ, Yehuda R, Liberzon I, Koenen KC, Jovanovic T, Kellis M, Miller MW, Bacanu SA, Nievergelt CM, Buxbaum JD, Sklar P, Ressler KJ, Stahl EA, Daskalakis NP.
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.
Published in:
Cell Reports
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