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

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 ide...

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Bibliographic Details
Main Authors: Huckins, Laura M., Chatzinakos, Chris, Breen, Michael S., Hartmann, Jakob, Klengel, Torsten, da Silva Almeida, Ana C., Dobbyn, Amanda, Girdhar, Kiran, Hoffman, Gabriel E., Klengel, Claudia, Logue, Mark W., Lori, Adriana, Maihofer, Adam X., Morrison, Filomene G., Nguyen, Hoang T., Park, YongJin, Ruderfer, Douglas, Sloofman, Laura G., van Rooij, Sanne J.H., Baker, Dewleen G., Chen, Chia-Yen, Cox, Nancy, Duncan, Laramie E., Geyer, Mark A., Glatt, Stephen J., Im, Hae Kyung, Risbrough, Victoria B., Smoller, Jordan W., Stein, Dan J., Yehuda, Rachel, Liberzon, Israel, Koenen, Karestan C., Jovanovic, Tanja, Kellis, Manolis, Miller, Mark W., Bacanu, Silviu-Alin, Nievergelt, Caroline M., Buxbaum, Joseph D., Sklar, Pamela, Ressler, Kerry J., Stahl, Eli A., Daskalakis, Nikolaos P., PTSD Working Group of Psychiatric Genomics Consortium
Other Authors: Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Format: Article
Language:English
Published: Elsevier BV 2021
Online Access:https://hdl.handle.net/1721.1/129399
Description
Summary: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.

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