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

Animals Case-Control Studies Cohort Studies Dexamethasone / pharmacology Down-Regulation / drug effects Gene Expression Regulation Gene Regulatory Networks Genetic Predisposition to Disease Humans Leukocytes / cytology Male Mice Mice, Inbred C57BL Military Personnel Prefrontal Cortex / metabolism RNA Interference RNA, Small Interfering / metabolism Repressor Proteins / blood Ribonucleoproteins, Small Nuclear / antagonists & inhibitors Stress Disorders, Post-Traumatic / blood
GWAS PTSD blood civilian glucocorticoid military prefrontal cortex sex splicing transcriptomic imputation

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
02 06 2020
Historique:
received: 06 03 2019
revised: 07 10 2019
accepted: 09 05 2020
entrez: 4 6 2020
pubmed: 4 6 2020
medline: 4 5 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2020.107716 PMID: 32492425 PMC: PMC7359754
pubmed: 32492425
pii: S2211-1247(20)30693-8
doi: 10.1016/j.celrep.2020.107716
pmc: PMC7359754
mid: NIHMS1600582
pii:
doi:

Substances chimiques

RNA, Small Interfering 0
Repressor Proteins 0
Ribonucleoproteins, Small Nuclear 0
SNRNP35 protein, human 0
ZNF140 protein, human 0
Dexamethasone 7S5I7G3JQL

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

107716

Subventions

Organisme : NCATS NIH HHS
ID : KL2 TR002542
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH117292
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH107666
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002541
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH118278
Pays : United States
Organisme : NIMH NIH HHS
ID : P50 MH115874
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH109536
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH124839
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101820
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH109539
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH106595
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020595
Pays : United States

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests J.W.S. is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. D.J.S. has received research grants and/or consultancy honoraria from Biocodex, Lundbeck, and Sun. R.Y. is a co-inventor of the following patent: “Genes associated with posttraumatic-stress disorder, WO 2010029176 A1.” I.L. has been a consultant for ARMGO Pharmaceuticals, Sunovion Pharmaceuticals, and Trimaran Pharma. K.J.R. has received consulting income from Alkermes and is on scientific advisory boards for Janssen, Verily, and Resilience Therapeutics. He has also received sponsored research support from Takeda and Brainsway. N.P.D. has held a part-time paid position at Cohen Veteran Bioscience. He has also been a consultant for Sunovion Pharmaceuticals.

Auteurs

Laura M Huckins (LM)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mental Illness Research, Education and Clinical Centers, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY 10468, USA. Electronic address: laura.huckins@mssm.edu.

Chris Chatzinakos (C)

Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Michael S Breen (MS)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Jakob Hartmann (J)

Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.

Torsten Klengel (T)

Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Goettingen 37075, Germany.

Ana C da Silva Almeida (AC)

Department of Biotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, 02142, USA.

Amanda Dobbyn (A)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Kiran Girdhar (K)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Gabriel E Hoffman (GE)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Claudia Klengel (C)

Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.

Mark W Logue (MW)

National Center for PTSD at VA Boston Healthcare System, Boston, MA 02130, USA; Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA; Biomedical Genetics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.

Adriana Lori (A)

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA.

Adam X Maihofer (AX)

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Center for Excellence in Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.

Filomene G Morrison (FG)

National Center for PTSD at VA Boston Healthcare System, Boston, MA 02130, USA; Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA.

Hoang T Nguyen (HT)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Yongjin Park (Y)

Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Douglas Ruderfer (D)

Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Laura G Sloofman (LG)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Sanne J H van Rooij (SJH)

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA.

Dewleen G Baker (DG)

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Center for Excellence in Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.

Chia-Yen Chen (CY)

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Psychiatric & Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Analytic and Translational Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Nancy Cox (N)

Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Laramie E Duncan (LE)

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.

Mark A Geyer (MA)

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Center for Excellence in Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.

Stephen J Glatt (SJ)

Department of Psychiatry and Behavioral Sciences, State University of New York - Upstate Medical University, Syracuse, NY, 13210, USA.

Hae Kyung Im (HK)

Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, IL 60637, USA; Center for Translational Data Science, The University of Chicago, Chicago, IL 60616, USA.

Victoria B Risbrough (VB)

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Center for Excellence in Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.

Jordan W Smoller (JW)

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Psychiatric & Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Analytic and Translational Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Dan J Stein (DJ)

SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town 7700, South Africa.

Rachel Yehuda (R)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mental Health Care Center, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY 10468, USA.

Israel Liberzon (I)

Department of Psychiatry and Behavioral Science, Texas A&M University College of Medicine, Bryan, TX 77807, USA.

Karestan C Koenen (KC)

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Psychiatric & Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Tanja Jovanovic (T)

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA; Department of Psychiatry and Behavioral Neuroscience, Wayne State University, Detroit, MI, USA.

Manolis Kellis (M)

Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Mark W Miller (MW)

National Center for PTSD at VA Boston Healthcare System, Boston, MA 02130, USA; Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA.

Silviu-Alin Bacanu (SA)

Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA.

Caroline M Nievergelt (CM)

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Center for Excellence in Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.

Joseph D Buxbaum (JD)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Pamela Sklar (P)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Kerry J Ressler (KJ)

Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.

Eli A Stahl (EA)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Nikolaos P Daskalakis (NP)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: ndaskalakis@mclean.harvard.edu.

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