Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts.
Laura M Huckins, Chris Chatzinakos, Michael S Breen, Jakob Hartmann, Torsten Klengel, Ana C da Silva Almeida, 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, PTSD Working Group of Psychiatric Genomics Consortium, Dewleen G Baker, Chia-Yen Chen, Nancy Cox, Laramie E Duncan, Mark A Geyer, Stephen J Glatt, Hae Kyung Im, Victoria B Risbrough, 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 Nievergelt, Joseph D Buxbaum, Pamela Sklar, Kerry J Ressler, Eli A Stahl, Nikolaos P Daskalakis
Cell reports 2020 Jun 02To 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. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Citation
Laura M Huckins, Chris Chatzinakos, Michael S Breen, Jakob Hartmann, Torsten Klengel, Ana C da Silva Almeida, 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, PTSD Working Group of Psychiatric Genomics Consortium, Dewleen G Baker, Chia-Yen Chen, Nancy Cox, Laramie E Duncan, Mark A Geyer, Stephen J Glatt, Hae Kyung Im, Victoria B Risbrough, 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 Nievergelt, Joseph D Buxbaum, Pamela Sklar, Kerry J Ressler, Eli A Stahl, Nikolaos P Daskalakis. Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts. Cell reports. 2020 Jun 02;31(9):107716
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PMID: 32492425
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