Cell Reports (Jun 2020)
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,
- 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
Affiliations
- Laura M. Huckins
- 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; Corresponding author
- Chris Chatzinakos
- 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
- 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
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA
- Torsten Klengel
- 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
- Department of Biotherapeutic and Medicinal Sciences, Biogen, Cambridge, MA, 02142, USA
- Amanda Dobbyn
- 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
- 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
- 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
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA
- Mark W. Logue
- 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
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA
- Adam X. Maihofer
- 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
- 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
- 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
- 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
- Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Laura G. Sloofman
- 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
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA
- Dewleen G. Baker
- 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
- 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
- Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Laramie E. Duncan
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
- Mark A. Geyer
- 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
- Department of Psychiatry and Behavioral Sciences, State University of New York – Upstate Medical University, Syracuse, NY, 13210, USA
- Hae Kyung Im
- 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
- 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
- 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
- SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town 7700, South Africa
- Rachel Yehuda
- 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
- Department of Psychiatry and Behavioral Science, Texas A&M University College of Medicine, Bryan, TX 77807, USA
- Karestan C. Koenen
- 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
- 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
- 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
- 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
- Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA
- Caroline M. Nievergelt
- 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
- 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
- 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
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA
- Eli A. Stahl
- 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
- 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; Corresponding author
- Journal volume & issue
-
Vol. 31,
no. 9
Abstract
Summary: 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.
