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

Abstract

PTSD has significant genetic heritability; however, it is unclear how genetic risk influences tissue-specific gene expression. We used brain and non-brain transcriptomic imputation models to impute genetically regulated gene expression (GReX) in 29,539 PTSD-cases and 166,145 controls from 70 unique PTSD cohorts and identified eighteen significant GReX-PTSD associations. The results suggest substantial genetic heterogeneity based on ancestry, cohort-type (military vs. civilian) and sex. The two study-wide significant PTSD-associations were identified in European (23195 cases/174642 controls) and military European cohorts (6004 cases/27538 controls); ZNF140 was predicted to be upregulated in whole blood and SNRNP35 was predicted to be downregulated in the BA9 region of the prefrontal cortex (PFC), respectively. Both associations were stronger in men compared to women. In peripheral leukocytes from 175 U.S. Marines, the observed PTSD differential gene expression correlated with the predicted blood GReX differences for these individuals, and deployment stress produced glucocorticoid- regulated expression changes that included downregulation of both ZNF140 and SNRNP35 expression. SNRNP35 is a subunit of the minor spliceosome complex and SNRNP35 knockdown in cells validated its functional importance in U12-intron splicing. Finally, mimicking acute activation of the endogenous stress axis with exogenous glucocorticoids in mice downregulated PFC Snrnp35 expression.