Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Journal: Nature genetics

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Affiliated Institutions:  Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. cnievergelt@ucsd.edu. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Biogen Inc.,Translational Sciences, Cambridge, MA, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. King's College London, National Institute for Health and Care Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK. Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. VA Connecticut Healthcare Center, West Haven, CT, USA. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, NY, USA. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA. The Danish Veteran Centre, Research and Knowledge Centre, Ringsted, Denmark. Oslo University Hospital, Division of Mental Health and Addiction, Oslo, Norway. Minneapolis VA Health Care System, Mental Health Service Line, Minneapolis, MN, USA. Duke University, Duke Molecular Physiology Institute, Durham, NC, USA. Boston Children's Hospital, Division of Adolescent and Young Adult Medicine, Boston, MA, USA. Department of Psychiatry, University Clinical Center of Tuzla, Tuzla, Bosnia and Herzegovina. Department of Psychiatry, University Clinical Center of Mostar, Mostar, Bosnia and Herzegovina. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA. Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA. Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil. Instituto Nacional de Psiquiatraía Ramón de la Fuente Muñiz, Center for Global Mental Health, Mexico City, Mexico. Medical College of Wisconsin, Comprehensive Injury Center, Milwaukee, WI, USA. Department of Psychiatry, James J. Peters VA Medical Center, Bronx, NY, USA. Department of Psychiatry, Washington University in Saint Louis School of Medicine, Saint Louis, MO, USA. Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, Cardiff, UK. Department of Psychiatry, Brain Center University Medical Center Utrecht, Utrecht, The Netherlands. Department of Psychiatry, Harvard Medical School, Boston, MA, USA. Department of Surgery, Division of Trauma & Acute Care Surgery, Medical College of Wisconsin, Milwaukee, WI, USA. King's College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK. Department of Psychiatry, Universidade Federal de São Paulo, Laboratory of Integrative Neuroscience, São Paulo, Brazil. University of New South Wales, School of Psychology, Sydney, New South Wales, Australia. Department of Internal Medicine, University of Michigan Medical School, Division of Pulmonary and Critical Care Medicine, Ann Arbor, MI, USA. Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, K. G. Jebsen Center for Genetic Epidemiology, Trondheim, Norway. Case Western Reserve University, School of Medicine, Cleveland, OH, USA. Chronic Diseases Research Centre (CEDOC), Lisbon Institute of Global Mental Health, Lisbon, Portugal. University of Toronto, CanPath National Coordinating Center, Toronto, Ontario, Canada. Stony Brook University, Family, Population, and Preventive Medicine, Stony Brook, NY, USA. QIMR Berghofer Medical Research Institute, Mental Health & Neuroscience Program, Brisbane, Queensland, Australia. Department of Genetics, Instituto Nacional de Psiquiatraía Ramón de la Fuente Muñiz, Mexico City, Mexico. Department of Radiology, Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. Department of Pathology, University of Cape Town, Division of Human Genetics, Cape Town, South Africa. Vanderbilt University Medical Center, Vanderbilt Genetics Institute, Nashville, TN, USA. University Hospital of Würzburg, Center of Mental Health, Psychiatry, Psychosomatics and Psychotherapy, Würzburg, Denmark. Department of Psychological Sciences, Kent State University, Kent, OH, USA. Minneapolis VA Health Care System, Research Service Line, Minneapolis, MN, USA. Huntsman Mental Health Institute, Salt Lake City, UT, USA. University of Freiburg, Faculty of Medicine, Centre for Basics in Neuromodulation, Freiburg, Denmark. University of Oslo, Institute of Clinical Medicine, Oslo, Norway. Department of Psychiatry, University Clinical Center of Sarajevo, Sarajevo, Bosnia and Herzegovina. Indiana University School of Medicine, Biochemistry and Molecular Biology, Indianapolis, IN, USA. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA. Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA. Department of Psychological Sciences, Case Western Reserve University, Cleveland, OH, USA. Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia. Boston University School of Public Health, Boston, MA, USA. VA Connecticut Healthcare Center, Psychiatry Service, West Haven, CT, USA. Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, The Netherlands. Department of Psychiatry, University Clinical Centre of Kosovo, Prishtina, Kosovo. Wayne State University School of Medicine, Psychiatry and Behavioral Neurosciencess, Detroit, MI, USA. Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia. Cohen Veterans Bioscience, New York City, NY, USA. Department of Genetics, Washington University in Saint Louis School of Medicine, Saint Louis, MO, USA. Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. University of Connecticut School of Medicine, Psychiatry, Farmington, CT, USA. University of Sydney, Brain and Mind Centre, Sydney, New South Wales, Australia. Department of Psychiatry, Yale University, New Haven, CT, USA. Department of Psychiatry, University Hospital Center of Zagreb, Zagreb, Croatia. Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA. Cardiff University, National Centre for Mental Health, Cardiff University Centre for Psychiatric Genetics and Genomics, Cardiff, UK. Centre for Addiction and Mental Health, Neurogenetics Section, Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Toronto, Ontario, Canada. Department of Health Care Policy, Harvard Medical School, Boston, MA, USA. The Ohio State University, College of Medicine, Institute for Behavioral Medicine Research, Columbus, OH, USA. University of Cape Town, Department of Psychiatry & Neuroscience Institute, SA MRC Unit on Risk & Resilience in Mental Disorders, Cape Town, South Africa. Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA. Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA. University of Tartu, Institute of Genomics, Estonian Genome Center, Tartu, Estonia. Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA. Queensland University of Technology, School of Biomedical Sciences, Kelvin Grove, Queensland, Australia. Department of Psychiatry and Behavioral Sciences, Texas A&M University College of Medicine, Bryan, TX, USA. Department of Anesthesiology, UNC Institute for Trauma Recovery, Chapel Hill, NC, USA. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Department of Medicine, Stony Brook University, Stony Brook, NY, USA. Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, The Netherlands. Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. New York University, Grossman School of Medicine, New York City, NY, USA. QIMR Berghofer Medical Research Institute, Genetics, Brisbane, Queensland, Australia. University of Adelaide, Discipline of Psychiatry, Adelaide, South Australia, Australia. Department of Psychology, Harvard University, Boston, MA, USA. Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA. VA Boston Healthcare System, GRECC/TRACTS, Boston, MA, USA. Boston University School of Medicine, Psychiatry, Biomedical Genetics, Boston, MA, USA. Duke University School of Medicine, Duke Brain Imaging and Analysis Center, Durham, NC, USA. Department of Emergency Medicine, Alpert Brown Medical School, Providence, RI, USA. Department of Psychiatry, University of Melbourne, Phoenix Australia, Melbourne, Victoria, Australia. Department of Psychology, Northern Illinois University, DeKalb, IL, USA. Universidade Federal de São Paulo, Psychiatry, São Paulo, Brazil. University of Nebraska Medical Center, College of Public Health, Omaha, NE, USA. South Texas Veterans Health Care System, Research and Development Service, San Antonio, TX, USA. Department of Psychology, University of Washington, Seattle, WA, USA. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Department of Psychological Sciences, Emory University, Atlanta, GA, USA. Department of Psychiatry, University of Washington, Seattle, WA, USA. Department of Nursing, Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA. Department of Epidemiology, Louisiana State University Health Sciences Center, School of Public Health, New Orleans, LA, USA. Biogen Inc., Research & Development, Cambridge, MA, USA. Department of Psychiatry and Neuropsychology, Maastricht Universitair Medisch Centrum, School for Mental Health and Neuroscience, Maastricht, The Netherlands. SUNY Downstate Health Sciences University, School of Public Health, Brooklyn, NY, USA. Child Mind Institute, New York City, NY, USA. Department of Medicine, Universidad Peruana de Ciencias Aplicadas, Lima, Peru. Universidade Federal de São Paulo, Departamento de Bioquímica-Disciplina de Biologia Molecular, São Paulo, Brazil. Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA. Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA. Department of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Oslo University Hospital, Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo, Norway. Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA. Mental Health Centre Sct. Hans, Institute of Biological Psychiatry, Roskilde, Denmark. University of South Florida College of Public Health, Genomics Program, Tampa, FL, USA. Department of Psychiatry, Uniformed Services University, Bethesda, MD, USA. Karolinska Institutet, Unit of Integrative Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden. University of Adelaide, Adelaide Medical School, Adelaide, South Australia, Australia. ARQ Nationaal Psychotrauma Centrum, Psychotrauma Research Expert Group, Diemen, The Netherlands. Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, The Netherlands. Department of Psychology, University of Oslo, Lifespan Changes in Brain and Cognition (LCBC), Oslo, Norway. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA. Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA. Department of Anthropology, University of Toronto, Dalla Lana School of Public Health, Toronto, Ontario, Canada. VA Boston Healthcare System, National Center for PTSD, Boston, MA, USA. Central Texas Veterans Health Care System, Research Service, Temple, TX, USA. Queensland University of Technology, School of Clinical Sciences, Kelvin Grove, Queensland, Australia. Department of Biostatistics, Yale University, New Haven, CT, USA.

Abstract summary 

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Authors & Co-authors:  Nievergelt Caroline M CM Maihofer Adam X AX Atkinson Elizabeth G EG Chen Chia-Yen CY Choi Karmel W KW Coleman Jonathan R I JRI Daskalakis Nikolaos P NP Duncan Laramie E LE Polimanti Renato R Aaronson Cindy C Amstadter Ananda B AB Andersen Soren B SB Andreassen Ole A OA Arbisi Paul A PA Ashley-Koch Allison E AE Austin S Bryn SB Avdibegoviç Esmina E Babić Dragan D Bacanu Silviu-Alin SA Baker Dewleen G DG Batzler Anthony A Beckham Jean C JC Belangero Sintia S Benjet Corina C Bergner Carisa C Bierer Linda M LM Biernacka Joanna M JM Bierut Laura J LJ Bisson Jonathan I JI Boks Marco P MP Bolger Elizabeth A EA Brandolino Amber A Breen Gerome G Bressan Rodrigo Affonseca RA Bryant Richard A RA Bustamante Angela C AC Bybjerg-Grauholm Jonas J Bækvad-Hansen Marie M Børglum Anders D AD Børte Sigrid S Cahn Leah L Calabrese Joseph R JR Caldas-de-Almeida Jose Miguel JM Chatzinakos Chris C Cheema Sheraz S Clouston Sean A P SAP Colodro-Conde Lucía L Coombes Brandon J BJ Cruz-Fuentes Carlos S CS Dale Anders M AM Dalvie Shareefa S Davis Lea K LK Deckert Jürgen J Delahanty Douglas L DL Dennis Michelle F MF Desarnaud Frank F DiPietro Christopher P CP Disner Seth G SG Docherty Anna R AR Domschke Katharina K Dyb Grete G Kulenović Alma Džubur AD Edenberg Howard J HJ Evans Alexandra A Fabbri Chiara C Fani Negar N Farrer Lindsay A LA Feder Adriana A Feeny Norah C NC Flory Janine D JD Forbes David D Franz Carol E CE Galea Sandro S Garrett Melanie E ME Gelaye Bizu B Gelernter Joel J Geuze Elbert E Gillespie Charles F CF Goleva Slavina B SB Gordon Scott D SD Goçi Aferdita A Grasser Lana Ruvolo LR Guindalini Camila C Haas Magali M Hagenaars Saskia S Hauser Michael A MA Heath Andrew C AC Hemmings Sian M J SMJ Hesselbrock Victor V Hickie Ian B IB Hogan Kelleigh K Hougaard David Michael DM Huang Hailiang H Huckins Laura M LM Hveem Kristian K Jakovljević Miro M Javanbakht Arash A Jenkins Gregory D GD Johnson Jessica J Jones Ian I Jovanovic Tanja T Karstoft Karen-Inge KI Kaufman Milissa L ML Kennedy James L JL Kessler Ronald C RC Khan Alaptagin A Kimbrel Nathan A NA King Anthony P AP Koen Nastassja N Kotov Roman R Kranzler Henry R HR Krebs Kristi K Kremen William S WS Kuan Pei-Fen PF Lawford Bruce R BR Lebois Lauren A M LAM Lehto Kelli K Levey Daniel F DF Lewis Catrin C Liberzon Israel I Linnstaedt Sarah D SD Logue Mark W MW Lori Adriana A Lu Yi Y Luft Benjamin J BJ Lupton Michelle K MK Luykx Jurjen J JJ Makotkine Iouri I Maples-Keller Jessica L JL Marchese Shelby S Marmar Charles C Martin Nicholas G NG Martínez-Levy Gabriela A GA McAloney Kerrie K McFarlane Alexander A McLaughlin Katie A KA McLean Samuel A SA Medland Sarah E SE Mehta Divya D Meyers Jacquelyn J Michopoulos Vasiliki V Mikita Elizabeth A EA Milani Lili L Milberg William W Miller Mark W MW Morey Rajendra A RA Morris Charles Phillip CP Mors Ole O Mortensen Preben Bo PB Mufford Mary S MS Nelson Elliot C EC Nordentoft Merete M Norman Sonya B SB Nugent Nicole R NR O'Donnell Meaghan M Orcutt Holly K HK Pan Pedro M PM Panizzon Matthew S MS Pathak Gita A GA Peters Edward S ES Peterson Alan L AL Peverill Matthew M Pietrzak Robert H RH Polusny Melissa A MA Porjesz Bernice B Powers Abigail A Qin Xue-Jun XJ Ratanatharathorn Andrew A Risbrough Victoria B VB Roberts Andrea L AL Rothbaum Alex O AO Rothbaum Barbara O BO Roy-Byrne Peter P Ruggiero Kenneth J KJ Rung Ariane A Runz Heiko H Rutten Bart P F BPF de Viteri Stacey Saenz SS Salum Giovanni Abrahão GA Sampson Laura L Sanchez Sixto E SE Santoro Marcos M Seah Carina C Seedat Soraya S Seng Julia S JS Shabalin Andrey A Sheerin Christina M CM Silove Derrick D Smith Alicia K AK Smoller Jordan W JW Sponheim Scott R SR Stein Dan J DJ Stensland Synne S Stevens Jennifer S JS Sumner Jennifer A JA Teicher Martin H MH Thompson Wesley K WK Tiwari Arun K AK Trapido Edward E Uddin Monica M Ursano Robert J RJ Valdimarsdóttir Unnur U Van Hooff Miranda M Vermetten Eric E Vinkers Christiaan H CH Voisey Joanne J Wang Yunpeng Y Wang Zhewu Z Waszczuk Monika M Weber Heike H Wendt Frank R FR Werge Thomas T Williams Michelle A MA Williamson Douglas E DE Winsvold Bendik S BS Winternitz Sherry S Wolf Christiane C Wolf Erika J EJ Xia Yan Y Xiong Ying Y Yehuda Rachel R Young Keith A KA Young Ross McD RM Zai Clement C CC Zai Gwyneth C GC Zervas Mark M Zhao Hongyu H Zoellner Lori A LA Zwart John-Anker JA deRoon-Cassini Terri T van Rooij Sanne J H SJH van den Heuvel Leigh L LL Stein Murray B MB Ressler Kerry J KJ Koenen Karestan C KC

Study Outcome 

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Citations :  Koenen, K. C. et al. Posttraumatic stress disorder in the World Mental Health Surveys. Psychol. Med. 47, 2260–2274 (2017).
Authors :  239
Identifiers
Doi : 10.1038/s41588-024-01707-9
SSN : 1546-1718
Study Population
Male,Female
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Other Terms
Study Design
Study Approach
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Publication Country
United States