Analysis of Genetically Regulated Gene Expression identifies a trauma type specific PTSD gene, SNRNP35-Reference-Cited by-同舟云学术

Analysis of Genetically Regulated Gene Expression identifies a trauma type specific PTSD gene, SNRNP35

Published:2019-03-19 Issue: Volume: Page:
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Huckins Laura M^ORCID,Breen Michael S^ORCID,Chatzinakos Chris^ORCID,Hartmann Jakob^ORCID,Klengel Torsten^ORCID,da Silva Almeida Ana C,Dobbyn Amanda^ORCID,Girdhar Kiran^ORCID,Hoffman Gabriel E^ORCID,Klengel Claudia,Logue Mark W,Lori Adriana^ORCID,Morrison Filomene G^ORCID,Nguyen Hoang T,Park Yongjin^ORCID,Ruderfer Douglas^ORCID,Sloofman Laura G^ORCID,van Rooij Sanne JH^ORCID,Baker Dewleen G^ORCID,Chen Chia-Yen^ORCID,Cox Nancy^ORCID,Duncan Laramie E^ORCID,Geyer Mark A^ORCID,Glatt Stephen J.^ORCID,Im Hae Kyung^ORCID,Maihofer Adam X^ORCID,Risbrough Victoria B^ORCID,Smoller Jordan W^ORCID,Stein Dan J^ORCID,Yehuda Rachel^ORCID,Liberzon Israel^ORCID,Koenen Karestan C^ORCID,Jovanovic Tanja^ORCID,Kellis Manolis^ORCID,Miller Mark W^ORCID,Bacanu Silviu-Alin^ORCID,Nievergelt Caroline M^ORCID,Buxbaum Joseph D^ORCID,Sklar Pamela^ORCID,Ressler Kerry J^ORCID,Stahl Eli A^ORCID,Daskalakis Nikolaos P^ORCID,

Abstract

SUMMARYPTSD 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 9,087 PTSD-cases and 23,811 controls and identified thirteen significant GReX-PTSD associations. The results suggest substantial genetic heterogeneity between civilian and military PTSD cohorts. The top study-wide significant PTSD-association was with predicted downregulation of the Small Nuclear Ribonucleoprotein U11/U12 Subunit 35 (SNRNP35) in the BA9 region of the prefrontal cortex (PFC) in military cohorts. 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 downregulatedSNRNP35expression, primarily in Marines with post-deployment PTSD. SNRNP35 is a subunit of the minor spliceosome complex andSNRNP35knockdown in cells validated its functional importance in U12-intron splicing. Finally, mimicking acute activation of the endogenous stress axis in mice downregulated PFCSnrnp35expression.

Publisher

Cold Spring Harbor Laboratory

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