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

PTSD Working Group of Psychiatric Genomics Consortium

doi:10.1016/j.celrep.2020.107716

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

PTSD Working Group of Psychiatric Genomics Consortium

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

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.

Original language	English (US)
Article number	107716
Pages (from-to)	107716
Journal	Cell Reports
Volume	31
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2020.107716
State	Published - Jun 2 2020

Keywords

GWAS
PTSD
blood
civilian
glucocorticoid
military
prefrontal cortex
sex
splicing
transcriptomic imputation

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2020.107716

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@article{ee936235c9044876a6d1e65afac648fd,

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

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.",

keywords = "GWAS, PTSD, blood, civilian, glucocorticoid, military, prefrontal cortex, sex, splicing, transcriptomic imputation",

author = "{PTSD Working Group of Psychiatric Genomics Consortium} and Huckins, {Laura M.} and Chris Chatzinakos and Breen, {Michael S.} and Jakob Hartmann and Torsten Klengel and {da Silva Almeida}, {Ana C.} and Amanda Dobbyn and Kiran Girdhar and Hoffman, {Gabriel E.} and Claudia Klengel and Logue, {Mark W.} and Adriana Lori and Maihofer, {Adam X.} and Morrison, {Filomene G.} and Nguyen, {Hoang T.} and Yongjin Park and Douglas Ruderfer and Sloofman, {Laura G.} and {van Rooij}, {Sanne J.H.} and Baker, {Dewleen G.} and Chen, {Chia Yen} and Nancy Cox and Duncan, {Laramie E.} and Geyer, {Mark A.} and Glatt, {Stephen J.} and Im, {Hae Kyung} and Risbrough, {Victoria B.} and Smoller, {Jordan W.} and Stein, {Dan J.} and Rachel Yehuda and Israel Liberzon and Koenen, {Karestan C.} and Tanja Jovanovic and Manolis Kellis and Miller, {Mark W.} and Bacanu, {Silviu Alin} and Nievergelt, {Caroline M.} and Buxbaum, {Joseph D.} and Pamela Sklar and Ressler, {Kerry J.} and Stahl, {Eli A.} and Daskalakis, {Nikolaos P.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = jun,

day = "2",

doi = "10.1016/j.celrep.2020.107716",

language = "English (US)",

volume = "31",

pages = "107716",

journal = "Cell Reports",

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publisher = "Cell Press",

number = "9",

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T1 - Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts

AU - PTSD Working Group of Psychiatric Genomics Consortium

AU - Huckins, Laura M.

AU - Chatzinakos, Chris

AU - Breen, Michael S.

AU - Hartmann, Jakob

AU - Klengel, Torsten

AU - da Silva Almeida, Ana C.

AU - Dobbyn, Amanda

AU - Girdhar, Kiran

AU - Hoffman, Gabriel E.

AU - Klengel, Claudia

AU - Logue, Mark W.

AU - Lori, Adriana

AU - Maihofer, Adam X.

AU - Morrison, Filomene G.

AU - Nguyen, Hoang T.

AU - Park, Yongjin

AU - Ruderfer, Douglas

AU - Sloofman, Laura G.

AU - van Rooij, Sanne J.H.

AU - Baker, Dewleen G.

AU - Chen, Chia Yen

AU - Cox, Nancy

AU - Duncan, Laramie E.

AU - Geyer, Mark A.

AU - Glatt, Stephen J.

AU - Im, Hae Kyung

AU - Risbrough, Victoria B.

AU - Smoller, Jordan W.

AU - Stein, Dan J.

AU - Yehuda, Rachel

AU - Liberzon, Israel

AU - Koenen, Karestan C.

AU - Jovanovic, Tanja

AU - Kellis, Manolis

AU - Miller, Mark W.

AU - Bacanu, Silviu Alin

AU - Nievergelt, Caroline M.

AU - Buxbaum, Joseph D.

AU - Sklar, Pamela

AU - Ressler, Kerry J.

AU - Stahl, Eli A.

AU - Daskalakis, Nikolaos P.

PY - 2020/6/2

Y1 - 2020/6/2

N2 - 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.

AB - 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.

KW - GWAS

KW - PTSD

KW - blood

KW - civilian

KW - glucocorticoid

KW - military

KW - prefrontal cortex

KW - sex

KW - splicing

KW - transcriptomic imputation

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U2 - 10.1016/j.celrep.2020.107716

DO - 10.1016/j.celrep.2020.107716

M3 - Article

C2 - 32492425

AN - SCOPUS:85085571507

SN - 2211-1247

VL - 31

SP - 107716

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 107716

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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