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

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

doi:10.1016/j.celrep.2020.107716

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

Cell Rep. 2020 Jun 2;31(9):107716. doi: 10.1016/j.celrep.2020.107716.

Authors

Laura M Huckins¹, Chris Chatzinakos², Michael S Breen³, Jakob Hartmann⁴, Torsten Klengel⁵, Ana C da Silva Almeida⁶, Amanda Dobbyn⁷, Kiran Girdhar⁷, Gabriel E Hoffman⁷, Claudia Klengel⁴, Mark W Logue⁸, Adriana Lori⁹, Adam X Maihofer¹⁰, Filomene G Morrison¹¹, Hoang T Nguyen⁷, Yongjin Park¹², Douglas Ruderfer¹³, Laura G Sloofman⁷, Sanne J H van Rooij⁹; PTSD Working Group of Psychiatric Genomics Consortium; Dewleen G Baker¹⁴, Chia-Yen Chen¹⁵, Nancy Cox¹³, Laramie E Duncan¹⁶, Mark A Geyer¹⁰, Stephen J Glatt¹⁷, Hae Kyung Im¹⁸, Victoria B Risbrough¹⁰, Jordan W Smoller¹⁵, Dan J Stein¹⁹, Rachel Yehuda²⁰, Israel Liberzon²¹, Karestan C Koenen²², Tanja Jovanovic²³, Manolis Kellis¹², Mark W Miller¹¹, Silviu-Alin Bacanu²⁴, Caroline M Nievergelt¹⁰, Joseph D Buxbaum²⁵, Pamela Sklar²⁶, Kerry J Ressler⁴, Eli A Stahl⁷, Nikolaos P Daskalakis²⁷

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
⁵ Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Goettingen 37075, Germany.
⁶ Department of Biotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, 02142, USA.
⁷ 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.
⁸ 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.
⁹ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA.
¹⁰ 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.
¹¹ 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.
¹² Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹³ Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁴ 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.
¹⁵ 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.
¹⁶ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
¹⁷ Department of Psychiatry and Behavioral Sciences, State University of New York - Upstate Medical University, Syracuse, NY, 13210, USA.
¹⁸ 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.
¹⁹ SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town 7700, South Africa.
²⁰ 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.
²¹ Department of Psychiatry and Behavioral Science, Texas A&M University College of Medicine, Bryan, TX 77807, USA.
²² 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.
²³ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA; Department of Psychiatry and Behavioral Neuroscience, Wayne State University, Detroit, MI, USA.
²⁴ Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA.
²⁵ 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.
²⁶ 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.
²⁷ 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.

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.

Publication types

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

MeSH terms

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
Leukocytes / metabolism
Male
Mice
Mice, Inbred C57BL
Military Personnel
Prefrontal Cortex / metabolism*
RNA Interference
RNA, Small Interfering / metabolism
Repressor Proteins / blood
Repressor Proteins / metabolism
Ribonucleoproteins, Small Nuclear / antagonists & inhibitors
Ribonucleoproteins, Small Nuclear / genetics*
Ribonucleoproteins, Small Nuclear / metabolism
Stress Disorders, Post-Traumatic / blood
Stress Disorders, Post-Traumatic / diagnosis
Stress Disorders, Post-Traumatic / genetics*

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding