Meta-Analysis

. 2019 Oct 8;10(1):4558.

doi: 10.1038/s41467-019-12576-w.

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

Caroline M Nievergelt^{1

2

3}, Adam X Maihofer^{4

5

6}, Torsten Klengel^{7

8

9}, Elizabeth G Atkinson^{10

11}, Chia-Yen Chen^{10

11

12}, Karmel W Choi^{10

13

14}, Jonathan R I Coleman^{15

16}, Shareefa Dalvie¹⁷, Laramie E Duncan¹⁸, Joel Gelernter^{19

20

21}, Daniel F Levey^{21

22}, Mark W Logue²³, Renato Polimanti^{21

22}, Allison C Provost²⁴, Andrew Ratanatharathorn¹⁴, Murray B Stein^{4

25

26}, Katy Torres^{4

5

6}, Allison E Aiello²⁷, Lynn M Almli²⁸, Ananda B Amstadter²⁹, Søren B Andersen³⁰, Ole A Andreassen³¹, Paul A Arbisi³², Allison E Ashley-Koch³³, S Bryn Austin^{7

34

35

36}, Esmina Avdibegovic³⁷, Dragan Babić³⁸, Marie Bækvad-Hansen^{39

40}, Dewleen G Baker^{4

5

26}, Jean C Beckham^{41

42

43}, Laura J Bierut⁴⁴, Jonathan I Bisson⁴⁵, Marco P Boks⁴⁶, Elizabeth A Bolger^{7

8}, Anders D Børglum^{40

47

48}, Bekh Bradley^{28

49}, Megan Brashear⁵⁰, Gerome Breen^{15

16}, Richard A Bryant⁵¹, Angela C Bustamante⁵², Jonas Bybjerg-Grauholm^{39

40}, Joseph R Calabrese⁵³, José M Caldas-de-Almeida⁵⁴, Anders M Dale⁵⁵, Mark J Daly¹², Nikolaos P Daskalakis^{7

8

24

56}, Jürgen Deckert⁵⁷, Douglas L Delahanty^{58

59}, Michelle F Dennis^{41

42

43}, Seth G Disner⁶⁰, Katharina Domschke^{61

62}, Alma Dzubur-Kulenovic⁶³, Christopher R Erbes^{64

65}, Alexandra Evans⁶⁶, Lindsay A Farrer⁶⁷, Norah C Feeny⁶⁸, Janine D Flory⁵⁶, David Forbes⁶⁹, Carol E Franz⁴, Sandro Galea⁷⁰, Melanie E Garrett⁴², Bizu Gelaye¹⁴, Elbert Geuze^{71

72}, Charles Gillespie²⁸, Aferdita Goci Uka⁷³, Scott D Gordon⁷⁴, Guia Guffanti^{7

8}, Rasha Hammamieh⁷⁵, Supriya Harnal¹⁰, Michael A Hauser⁴², Andrew C Heath⁷⁶, Sian M J Hemmings⁷⁷, David Michael Hougaard^{39

40}, Miro Jakovljevic⁷⁸, Marti Jett⁷⁵, Eric Otto Johnson⁷⁹, Ian Jones⁶⁶, Tanja Jovanovic²⁸, Xue-Jun Qin³³, Angela G Junglen⁵⁸, Karen-Inge Karstoft^{30

80}, Milissa L Kaufman^{7

8}, Ronald C Kessler⁷, Alaptagin Khan^{8

81}, Nathan A Kimbrel^{33

41

43}, Anthony P King⁸², Nastassja Koen¹⁷, Henry R Kranzler^{83

84}, William S Kremen^{4

5}, Bruce R Lawford^{85

86}, Lauren A M Lebois^{7

8}, Catrin E Lewis⁶⁶, Sarah D Linnstaedt⁸⁷, Adriana Lori⁸⁸, Bozo Lugonja⁶⁶, Jurjen J Luykx^{46

72}, Michael J Lyons⁸⁹, Jessica Maples-Keller²⁸, Charles Marmar⁹⁰, Alicia R Martin^{10

11}, Nicholas G Martin⁷⁴, Douglas Maurer⁹¹, Matig R Mavissakalian⁵³, Alexander McFarlane⁹², Regina E McGlinchey⁹³, Katie A McLaughlin⁹⁴, Samuel A McLean^{87

95}, Sarah McLeay⁹⁶, Divya Mehta^{85

97}, William P Milberg⁹³, Mark W Miller²³, Rajendra A Morey³³, Charles Phillip Morris^{85

86}, Ole Mors^{40

98}, Preben B Mortensen^{40

47

99

100}, Benjamin M Neale^{10

11}, Elliot C Nelson⁴⁴, Merete Nordentoft^{40

101}, Sonya B Norman^{4

102

103}, Meaghan O'Donnell⁶⁹, Holly K Orcutt¹⁰⁴, Matthew S Panizzon⁴, Edward S Peters⁵⁰, Alan L Peterson¹⁰⁵, Matthew Peverill¹⁰⁶, Robert H Pietrzak^{22

107}, Melissa A Polusny^{64

108

109}, John P Rice⁴⁴, Stephan Ripke^{10

12

110}, Victoria B Risbrough^{4

5

6}, Andrea L Roberts¹¹¹, Alex O Rothbaum⁶⁸, Barbara O Rothbaum²⁸, Peter Roy-Byrne¹⁰⁶, Ken Ruggiero¹¹², Ariane Rung⁵⁰, Bart P F Rutten¹¹³, Nancy L Saccone⁴⁴, Sixto E Sanchez¹¹⁴, Dick Schijven^{46

72}, Soraya Seedat⁷⁷, Antonia V Seligowski^{7

8}, Julia S Seng¹¹⁵, Christina M Sheerin²⁹, Derrick Silove¹¹⁶, Alicia K Smith^{28

88}, Jordan W Smoller^{10

11

13}, Scott R Sponheim^{32

64}, Dan J Stein¹⁷, Jennifer S Stevens²⁸, Jennifer A Sumner¹¹⁷, Martin H Teicher^{7

8}, Wesley K Thompson^{4

40

118

119}, Edward Trapido⁵⁰, Monica Uddin¹²⁰, Robert J Ursano¹²¹, Leigh Luella van den Heuvel⁷⁷, Miranda Van Hooff⁹², Eric Vermetten^{90

122

123

124}, Christiaan H Vinkers^{125

126}, Joanne Voisey^{85

86}, Yunpeng Wang^{40

118

119}, Zhewu Wang^{127

128}, Thomas Werge^{40

118

129}, Michelle A Williams¹⁴, Douglas E Williamson^{41

42}, Sherry Winternitz^{7

8}, Christiane Wolf⁵⁷, Erika J Wolf²³, Jonathan D Wolff⁸, Rachel Yehuda^{56

130}, Ross McD Young^{85

97}, Keith A Young^{131

132}, Hongyu Zhao¹³³, Lori A Zoellner¹³⁴, Israel Liberzon⁸², Kerry J Ressler^{7

8

28}, Magali Haas²⁴, Karestan C Koenen^{10

12

135}

Affiliations

¹ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA. cnievergelt@ucsd.edu.
² Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA. cnievergelt@ucsd.edu.
³ Veterans Affairs San Diego Healthcare System, Research Service, San Diego, CA, USA. cnievergelt@ucsd.edu.
⁴ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA.
⁵ Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
⁶ Veterans Affairs San Diego Healthcare System, Research Service, San Diego, CA, USA.
⁷ Harvard Medical School, Department of Psychiatry, Boston, MA, USA.
⁸ McLean Hospital, Belmont, MA, USA.
⁹ University Medical Center Goettingen, Department of Psychiatry, Göttingen, DE, Germany.
¹⁰ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
¹¹ Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, MA, USA.
¹² Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA.
¹³ Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA.
¹⁴ Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA, USA.
¹⁵ King's College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, London, GB, USA.
¹⁶ King's College London, NIHR BRC at the Maudsley, London, GB, USA.
¹⁷ University of Cape Town, SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, Cape Town, Western Cape, ZA, USA.
¹⁸ Stanford University, Department of Psychiatry and Behavioral Sciences, Stanford, CA, USA.
¹⁹ US Department of Veterans Affairs, Department of Psychiatry, West Haven, CT, USA.
²⁰ Yale University School of Medicine, Department of Genetics and Neuroscience, New Haven, CT, USA.
²¹ VA Connecticut Healthcare Center, West Haven, CT, USA.
²² Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA.
²³ VA Boston Healthcare System, National Center for PTSD, Boston, MA, USA.
²⁴ Cohen Veterans Bioscience, Cambridge, MA, USA.
²⁵ Veterans Affairs San Diego Healthcare System, Million Veteran Program, San Diego, CA, USA.
²⁶ Veterans Affairs San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA.
²⁷ Gillings School of Global Public Health, Department of Epidemiology, Chapel Hill, NC, USA.
²⁸ Emory University, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA.
²⁹ Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Richmond, VA, USA.
³⁰ The Danish Veteran Centre, Research and Knowledge Centre, Ringsted, Sjaelland, Denmark.
³¹ University of Oslo, Institute of Clinical Medicine, Oslo, NO, Norway.
³² Minneapolis VA Health Care System, Mental Health Service Line, Minneapolis, MN, USA.
³³ Duke University, Duke Molecular Physiology Institute, Durham, NC, USA.
³⁴ Boston Children's Hospital, Division of Adolescent and Young Adult Medicine, Boston, MA, USA.
³⁵ Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, MA, USA.
³⁶ Harvard School of Public Health, Department of Social and Behavioral Sciences, Boston, MA, USA.
³⁷ University Clinical Center of Tuzla, Department of Psychiatry, Tuzla, BA, Bosnia and Herzegovina.
³⁸ University Clinical Center of Mostar, Department of Psychiatry, Mostar, BA, Bosnia and Herzegovina.
³⁹ Statens Serum Institut, Department for Congenital Disorders, Copenhagen, DK, Denmark.
⁴⁰ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, DK, Denmark.
⁴¹ Durham VA Medical Center, Research, Durham, NC, USA.
⁴² Duke University, Department of Psychiatry and Behavioral Sciences, Durham, NC, USA.
⁴³ VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC), Genetics Research Laboratory, Durham, NC, USA.
⁴⁴ Washington University in Saint Louis School of Medicine, Department of Psychiatry, Saint Louis, MO, USA.
⁴⁵ Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, Cardiff, UK.
⁴⁶ UMC Utrecht Brain Center Rudolf Magnus, Department of Translational Neuroscience, Utrecht, Utrecht, NL, Netherlands.
⁴⁷ Aarhus University, Centre for Integrative Sequencing, iSEQ, Aarhus, DK, Denmark.
⁴⁸ Aarhus University, Department of Biomedicine - Human Genetics, Aarhus, DK, Denmark.
⁴⁹ Atlanta VA Health Care System, Mental Health Service Line, Decatur, GA, USA.
⁵⁰ Louisiana State University Health Sciences Center, School of Public Health and Department of Epidemiology, New Orleans, LA, USA.
⁵¹ University of New South Wales, Department of Psychology, Sydney, NSW, Australia.
⁵² University of Michigan Medical School, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ann Arbor, MI, USA.
⁵³ University Hospitals, Department of Psychiatry, Cleveland, OH, USA.
⁵⁴ CEDOC -Chronic Diseases Research Centre, Lisbon Institute of Global Mental Health, Lisbon, PT, Portugal.
⁵⁵ University of California San Diego, Department of Radiology, Department of Neurosciences, La Jolla, CA, USA.
⁵⁶ Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, NY, USA.
⁵⁷ University Hospital of Würzburg, Center of Mental Health, Psychiatry, Psychosomatics and Psychotherapy, Würzburg, DE, Germany.
⁵⁸ Kent State University, Department of Psychological Sciences, Kent, OH, USA.
⁵⁹ Kent State University, Research and Sponsored Programs, Kent, OH, USA.
⁶⁰ Minneapolis VA Health Care System, Research Service Line, Minneapolis, MN, USA.
⁶¹ Medical Center-University of Freiburg, Faculty of Medicine, Department of Psychiatry and Psychotherapy, Freiburg, DE, Germany.
⁶² University of Freiburg, Faculty of Medicine, Centre for Basics in Neuromodulation, Freiburg, DE, Germany.
⁶³ University Clinical Center of Sarajevo, Department of Psychiatry, Sarajevo, BA, Bosnia and Herzegovina.
⁶⁴ University of Minnesota, Department of Psychiatry, Minneapolis, MN, USA.
⁶⁵ Minneapolis VA Health Care System, Center for Care Delivery and Outcomes Research (CCDOR), Minneapolis, MN, USA.
⁶⁶ Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, Cardiff, South Glamorgan, GB, USA.
⁶⁷ Boston University School of Medicine, Department of Medicine, Boston, MA, USA.
⁶⁸ Case Western Reserve University, Department of Psychological Sciences, Cleveland, OH, USA.
⁶⁹ University of Melbourne, Department of Psychiatry, Melbourne, VIC, AU, USA.
⁷⁰ Boston University, Department of Psychological and Brain Sciences, Boston, MA, USA.
⁷¹ Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, Utrecht, NL, Netherlands.
⁷² UMC Utrecht Brain Center Rudolf Magnus, Department of Psychiatry, Utrecht, Utrecht, NL, Netherlands.
⁷³ University Clinical Centre of Kosovo, Department of Psychiatry, Prishtina, Kosovo, XK, USA.
⁷⁴ QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, Queensland, Australia.
⁷⁵ US Army Medical Research and Materiel Command, USACEHR, Fort Detrick, MD, USA.
⁷⁶ Washington University in Saint Louis School of Medicine, Department of Genetics, Saint Louis, MO, USA.
⁷⁷ Stellenbosch University Faculty of Medicine and Health Sciences, Department of Psychiatry, Cape Town, Western Cape, ZA, South Africa.
⁷⁸ University Hospital Center of Zagreb, Department of Psychiatry, Zagreb, HR, USA.
⁷⁹ RTI International, Behavioral Health and Criminal Justice Division, Research Triangle Park, NC, USA.
⁸⁰ University of Copenhagen, Department of Psychology, Copenhagen, DK, Denmark.
⁸¹ Harvard Medical School, Department of Health Care Policy, Boston, MA, USA.
⁸² University of Michigan Medical School, Department of Psychiatry, Ann Arbor, MI, USA.
⁸³ University of Pennsylvania Perelman School of Medicine, Department of Psychiatry, Philadelphia, PA, USA.
⁸⁴ Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA.
⁸⁵ Queensland University of Technology, Institute of Health and Biomedical Innovation, Kelvin Grove, QLD, AU, Australia.
⁸⁶ Queensland University of Technology, School of Biomedical Sciences, Kelvin Grove, QLD, AU, Australia.
⁸⁷ UNC Institute for Trauma Recovery, Department of Anesthesiology, Chapel Hill, NC, USA.
⁸⁸ Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, USA.
⁸⁹ Boston University, Dean's Office, Boston, MA, USA.
⁹⁰ New York University School of Medicine, Department of Psychiatry, New York, NY, USA.
⁹¹ United States Army, Command, Fort Sill, OK, USA.
⁹² University of Adelaide, Department of Psychiatry, Adelaide, South Australia, AU, Australia.
⁹³ VA Boston Health Care System, GRECC/TRACTS, Boston, MA, USA.
⁹⁴ Harvard University, Department of Psychology, Boston, MA, USA.
⁹⁵ UNC Institute for Trauma Recovery, Department of Emergency Medicine, Chapel Hill, NC, USA.
⁹⁶ Gallipoli Medical Research Institute, PTSD Initiative, Greenslopes, Queensland, AU, Australia.
⁹⁷ Queensland University of Technology, School of Psychology and Counseling, Faculty of Health, Kelvin Grove, QLD, AU, Australia.
⁹⁸ Aarhus University Hospital, Psychosis Research Unit, Risskov, DK, Denmark.
⁹⁹ Aarhus University, Centre for Integrated Register-based Research, Aarhus, DK, Denmark.
¹⁰⁰ Aarhus University, National Centre for Register-Based Research, Aarhus, DK, Denmark.
¹⁰¹ University of Copenhagen, Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, Copenhagen, DK, Denmark.
¹⁰² Veterans Affairs San Diego Healthcare System, Department of Research and Psychiatry, San Diego, CA, USA.
¹⁰³ National Center for Post Traumatic Stress Disorder, Executive Division, White River Junction, San Diego, VT, USA.
¹⁰⁴ Northern Illinois University, Department of Psychology, DeKalb, IL, USA.
¹⁰⁵ University of Texas Health Science Center at San Antonio, Department of Psychiatry, San Antonio, TX, USA.
¹⁰⁶ University of Washington, Department of Psychology, Seattle, WA, USA.
¹⁰⁷ U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, West Haven, CT, USA.
¹⁰⁸ Minneapolis VA Health Care System, Department of Mental Health, Minneapolis, MN, USA.
¹⁰⁹ Minneapolis VA Health Care System, Department of Psychology, Minneapolis, MN, USA.
¹¹⁰ Charité - Universitätsmedizin, Department of Psychiatry and Psychotherapy, Berlin, GE, Germany.
¹¹¹ Harvard T.H. Chan School of Public Health, Department of Environmental Health, Boston, MA, USA.
¹¹² Medical University of South Carolina, Department of Nursing and Department of Psychiatry, Charleston, SC, USA.
¹¹³ Maastricht Universitair Medisch Centrum, School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht, Limburg, NL, Netherlands.
¹¹⁴ Universidad Peruana de Ciencias Aplicadas Facultad de Ciencias de la Salud, Department of Medicine, Lima, Lima, PE, USA.
¹¹⁵ University of Michigan, School of Nursing, Ann Arbor, MI, USA.
¹¹⁶ University of New South Wales, Department of Psychiatry, Sydney, NSW, AU, USA.
¹¹⁷ Columbia University Medical Center, Department of Medicine, New York, NY, USA.
¹¹⁸ Mental Health Centre Sct. Hans, Institute of Biological Psychiatry, Roskilde, DK, Denmark.
¹¹⁹ Oslo University Hospital, KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo, NO, USA.
¹²⁰ University of South Florida College of Public Health, Genomics Program, Tampa, FL, USA.
¹²¹ Uniformed Services University, Department of Psychiatry, Bethesda, Maryland, USA.
¹²² Arq, Psychotrauma Reseach Expert Group, Diemen, NH, Netherlands.
¹²³ Leiden University Medical Center, Department of Psychiatry, Leiden, ZH, NL, Netherlands.
¹²⁴ Netherlands Defense Department, Research Center, Utrecht, UT, Netherlands.
¹²⁵ Amsterdam UMC (location VUmc), Department of Anatomy and Neurosciences, Amsterdam, Holland, NL, Netherlands.
¹²⁶ Amsterdam UMC (location VUmc), Department of Psychiatry, Amsterdam, Holland, NL, Netherlands.
¹²⁷ Ralph H Johnson VA Medical Center, Department of Mental Health, Charleston, SC, USA.
¹²⁸ Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, Charleston, SC, USA.
¹²⁹ University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark.
¹³⁰ James J Peters VA Medical Center, Department of Mental Health, Bronx, NY, USA.
¹³¹ Baylor Scott and White Central Texas, Department of Psychiatry, Temple, TX, USA.
¹³² CTVHCS, COE for Research on Returning War Veterans, Waco, TX, USA.
¹³³ Yale University, Department of Biostatistics, New Haven, CT, USA.
¹³⁴ University of Washington, Department of Psychiatry and Behavioral Sciences, Seattle, WA, USA.
¹³⁵ Harvard School of Public Health, Department of Epidemiology, Boston, MA, USA.

PMID: 31594949
PMCID: PMC6783435
DOI: 10.1038/s41467-019-12576-w

Meta-Analysis

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

Caroline M Nievergelt et al. Nat Commun. 2019.

. 2019 Oct 8;10(1):4558.

doi: 10.1038/s41467-019-12576-w.

Authors

Affiliations

¹ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA. cnievergelt@ucsd.edu.
² Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA. cnievergelt@ucsd.edu.
³ Veterans Affairs San Diego Healthcare System, Research Service, San Diego, CA, USA. cnievergelt@ucsd.edu.
⁴ University of California San Diego, Department of Psychiatry, La Jolla, CA, USA.
⁵ Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
⁶ Veterans Affairs San Diego Healthcare System, Research Service, San Diego, CA, USA.
⁷ Harvard Medical School, Department of Psychiatry, Boston, MA, USA.
⁸ McLean Hospital, Belmont, MA, USA.
⁹ University Medical Center Goettingen, Department of Psychiatry, Göttingen, DE, Germany.
¹⁰ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
¹¹ Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, MA, USA.
¹² Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Boston, MA, USA.
¹³ Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA.
¹⁴ Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, MA, USA.
¹⁵ King's College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, London, GB, USA.
¹⁶ King's College London, NIHR BRC at the Maudsley, London, GB, USA.
¹⁷ University of Cape Town, SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, Cape Town, Western Cape, ZA, USA.
¹⁸ Stanford University, Department of Psychiatry and Behavioral Sciences, Stanford, CA, USA.
¹⁹ US Department of Veterans Affairs, Department of Psychiatry, West Haven, CT, USA.
²⁰ Yale University School of Medicine, Department of Genetics and Neuroscience, New Haven, CT, USA.
²¹ VA Connecticut Healthcare Center, West Haven, CT, USA.
²² Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA.
²³ VA Boston Healthcare System, National Center for PTSD, Boston, MA, USA.
²⁴ Cohen Veterans Bioscience, Cambridge, MA, USA.
²⁵ Veterans Affairs San Diego Healthcare System, Million Veteran Program, San Diego, CA, USA.
²⁶ Veterans Affairs San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA.
²⁷ Gillings School of Global Public Health, Department of Epidemiology, Chapel Hill, NC, USA.
²⁸ Emory University, Department of Psychiatry and Behavioral Sciences, Atlanta, GA, USA.
²⁹ Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Richmond, VA, USA.
³⁰ The Danish Veteran Centre, Research and Knowledge Centre, Ringsted, Sjaelland, Denmark.
³¹ University of Oslo, Institute of Clinical Medicine, Oslo, NO, Norway.
³² Minneapolis VA Health Care System, Mental Health Service Line, Minneapolis, MN, USA.
³³ Duke University, Duke Molecular Physiology Institute, Durham, NC, USA.
³⁴ Boston Children's Hospital, Division of Adolescent and Young Adult Medicine, Boston, MA, USA.
³⁵ Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, MA, USA.
³⁶ Harvard School of Public Health, Department of Social and Behavioral Sciences, Boston, MA, USA.
³⁷ University Clinical Center of Tuzla, Department of Psychiatry, Tuzla, BA, Bosnia and Herzegovina.
³⁸ University Clinical Center of Mostar, Department of Psychiatry, Mostar, BA, Bosnia and Herzegovina.
³⁹ Statens Serum Institut, Department for Congenital Disorders, Copenhagen, DK, Denmark.
⁴⁰ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, DK, Denmark.
⁴¹ Durham VA Medical Center, Research, Durham, NC, USA.
⁴² Duke University, Department of Psychiatry and Behavioral Sciences, Durham, NC, USA.
⁴³ VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC), Genetics Research Laboratory, Durham, NC, USA.
⁴⁴ Washington University in Saint Louis School of Medicine, Department of Psychiatry, Saint Louis, MO, USA.
⁴⁵ Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, Cardiff, UK.
⁴⁶ UMC Utrecht Brain Center Rudolf Magnus, Department of Translational Neuroscience, Utrecht, Utrecht, NL, Netherlands.
⁴⁷ Aarhus University, Centre for Integrative Sequencing, iSEQ, Aarhus, DK, Denmark.
⁴⁸ Aarhus University, Department of Biomedicine - Human Genetics, Aarhus, DK, Denmark.
⁴⁹ Atlanta VA Health Care System, Mental Health Service Line, Decatur, GA, USA.
⁵⁰ Louisiana State University Health Sciences Center, School of Public Health and Department of Epidemiology, New Orleans, LA, USA.
⁵¹ University of New South Wales, Department of Psychology, Sydney, NSW, Australia.
⁵² University of Michigan Medical School, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ann Arbor, MI, USA.
⁵³ University Hospitals, Department of Psychiatry, Cleveland, OH, USA.
⁵⁴ CEDOC -Chronic Diseases Research Centre, Lisbon Institute of Global Mental Health, Lisbon, PT, Portugal.
⁵⁵ University of California San Diego, Department of Radiology, Department of Neurosciences, La Jolla, CA, USA.
⁵⁶ Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, NY, USA.
⁵⁷ University Hospital of Würzburg, Center of Mental Health, Psychiatry, Psychosomatics and Psychotherapy, Würzburg, DE, Germany.
⁵⁸ Kent State University, Department of Psychological Sciences, Kent, OH, USA.
⁵⁹ Kent State University, Research and Sponsored Programs, Kent, OH, USA.
⁶⁰ Minneapolis VA Health Care System, Research Service Line, Minneapolis, MN, USA.
⁶¹ Medical Center-University of Freiburg, Faculty of Medicine, Department of Psychiatry and Psychotherapy, Freiburg, DE, Germany.
⁶² University of Freiburg, Faculty of Medicine, Centre for Basics in Neuromodulation, Freiburg, DE, Germany.
⁶³ University Clinical Center of Sarajevo, Department of Psychiatry, Sarajevo, BA, Bosnia and Herzegovina.
⁶⁴ University of Minnesota, Department of Psychiatry, Minneapolis, MN, USA.
⁶⁵ Minneapolis VA Health Care System, Center for Care Delivery and Outcomes Research (CCDOR), Minneapolis, MN, USA.
⁶⁶ Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, Cardiff, South Glamorgan, GB, USA.
⁶⁷ Boston University School of Medicine, Department of Medicine, Boston, MA, USA.
⁶⁸ Case Western Reserve University, Department of Psychological Sciences, Cleveland, OH, USA.
⁶⁹ University of Melbourne, Department of Psychiatry, Melbourne, VIC, AU, USA.
⁷⁰ Boston University, Department of Psychological and Brain Sciences, Boston, MA, USA.
⁷¹ Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, Utrecht, NL, Netherlands.
⁷² UMC Utrecht Brain Center Rudolf Magnus, Department of Psychiatry, Utrecht, Utrecht, NL, Netherlands.
⁷³ University Clinical Centre of Kosovo, Department of Psychiatry, Prishtina, Kosovo, XK, USA.
⁷⁴ QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, Queensland, Australia.
⁷⁵ US Army Medical Research and Materiel Command, USACEHR, Fort Detrick, MD, USA.
⁷⁶ Washington University in Saint Louis School of Medicine, Department of Genetics, Saint Louis, MO, USA.
⁷⁷ Stellenbosch University Faculty of Medicine and Health Sciences, Department of Psychiatry, Cape Town, Western Cape, ZA, South Africa.
⁷⁸ University Hospital Center of Zagreb, Department of Psychiatry, Zagreb, HR, USA.
⁷⁹ RTI International, Behavioral Health and Criminal Justice Division, Research Triangle Park, NC, USA.
⁸⁰ University of Copenhagen, Department of Psychology, Copenhagen, DK, Denmark.
⁸¹ Harvard Medical School, Department of Health Care Policy, Boston, MA, USA.
⁸² University of Michigan Medical School, Department of Psychiatry, Ann Arbor, MI, USA.
⁸³ University of Pennsylvania Perelman School of Medicine, Department of Psychiatry, Philadelphia, PA, USA.
⁸⁴ Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA.
⁸⁵ Queensland University of Technology, Institute of Health and Biomedical Innovation, Kelvin Grove, QLD, AU, Australia.
⁸⁶ Queensland University of Technology, School of Biomedical Sciences, Kelvin Grove, QLD, AU, Australia.
⁸⁷ UNC Institute for Trauma Recovery, Department of Anesthesiology, Chapel Hill, NC, USA.
⁸⁸ Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, USA.
⁸⁹ Boston University, Dean's Office, Boston, MA, USA.
⁹⁰ New York University School of Medicine, Department of Psychiatry, New York, NY, USA.
⁹¹ United States Army, Command, Fort Sill, OK, USA.
⁹² University of Adelaide, Department of Psychiatry, Adelaide, South Australia, AU, Australia.
⁹³ VA Boston Health Care System, GRECC/TRACTS, Boston, MA, USA.
⁹⁴ Harvard University, Department of Psychology, Boston, MA, USA.
⁹⁵ UNC Institute for Trauma Recovery, Department of Emergency Medicine, Chapel Hill, NC, USA.
⁹⁶ Gallipoli Medical Research Institute, PTSD Initiative, Greenslopes, Queensland, AU, Australia.
⁹⁷ Queensland University of Technology, School of Psychology and Counseling, Faculty of Health, Kelvin Grove, QLD, AU, Australia.
⁹⁸ Aarhus University Hospital, Psychosis Research Unit, Risskov, DK, Denmark.
⁹⁹ Aarhus University, Centre for Integrated Register-based Research, Aarhus, DK, Denmark.
¹⁰⁰ Aarhus University, National Centre for Register-Based Research, Aarhus, DK, Denmark.
¹⁰¹ University of Copenhagen, Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, Copenhagen, DK, Denmark.
¹⁰² Veterans Affairs San Diego Healthcare System, Department of Research and Psychiatry, San Diego, CA, USA.
¹⁰³ National Center for Post Traumatic Stress Disorder, Executive Division, White River Junction, San Diego, VT, USA.
¹⁰⁴ Northern Illinois University, Department of Psychology, DeKalb, IL, USA.
¹⁰⁵ University of Texas Health Science Center at San Antonio, Department of Psychiatry, San Antonio, TX, USA.
¹⁰⁶ University of Washington, Department of Psychology, Seattle, WA, USA.
¹⁰⁷ U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, West Haven, CT, USA.
¹⁰⁸ Minneapolis VA Health Care System, Department of Mental Health, Minneapolis, MN, USA.
¹⁰⁹ Minneapolis VA Health Care System, Department of Psychology, Minneapolis, MN, USA.
¹¹⁰ Charité - Universitätsmedizin, Department of Psychiatry and Psychotherapy, Berlin, GE, Germany.
¹¹¹ Harvard T.H. Chan School of Public Health, Department of Environmental Health, Boston, MA, USA.
¹¹² Medical University of South Carolina, Department of Nursing and Department of Psychiatry, Charleston, SC, USA.
¹¹³ Maastricht Universitair Medisch Centrum, School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht, Limburg, NL, Netherlands.
¹¹⁴ Universidad Peruana de Ciencias Aplicadas Facultad de Ciencias de la Salud, Department of Medicine, Lima, Lima, PE, USA.
¹¹⁵ University of Michigan, School of Nursing, Ann Arbor, MI, USA.
¹¹⁶ University of New South Wales, Department of Psychiatry, Sydney, NSW, AU, USA.
¹¹⁷ Columbia University Medical Center, Department of Medicine, New York, NY, USA.
¹¹⁸ Mental Health Centre Sct. Hans, Institute of Biological Psychiatry, Roskilde, DK, Denmark.
¹¹⁹ Oslo University Hospital, KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo, NO, USA.
¹²⁰ University of South Florida College of Public Health, Genomics Program, Tampa, FL, USA.
¹²¹ Uniformed Services University, Department of Psychiatry, Bethesda, Maryland, USA.
¹²² Arq, Psychotrauma Reseach Expert Group, Diemen, NH, Netherlands.
¹²³ Leiden University Medical Center, Department of Psychiatry, Leiden, ZH, NL, Netherlands.
¹²⁴ Netherlands Defense Department, Research Center, Utrecht, UT, Netherlands.
¹²⁵ Amsterdam UMC (location VUmc), Department of Anatomy and Neurosciences, Amsterdam, Holland, NL, Netherlands.
¹²⁶ Amsterdam UMC (location VUmc), Department of Psychiatry, Amsterdam, Holland, NL, Netherlands.
¹²⁷ Ralph H Johnson VA Medical Center, Department of Mental Health, Charleston, SC, USA.
¹²⁸ Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, Charleston, SC, USA.
¹²⁹ University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark.
¹³⁰ James J Peters VA Medical Center, Department of Mental Health, Bronx, NY, USA.
¹³¹ Baylor Scott and White Central Texas, Department of Psychiatry, Temple, TX, USA.
¹³² CTVHCS, COE for Research on Returning War Veterans, Waco, TX, USA.
¹³³ Yale University, Department of Biostatistics, New Haven, CT, USA.
¹³⁴ University of Washington, Department of Psychiatry and Behavioral Sciences, Seattle, WA, USA.
¹³⁵ Harvard School of Public Health, Department of Epidemiology, Boston, MA, USA.

PMID: 31594949
PMCID: PMC6783435
DOI: 10.1038/s41467-019-12576-w

Abstract

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

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Conflict of interest statement

L.J.B., J.P.R., and the spouse of N.L.S. are listed as inventors on Issued U.S. Patent 8,080,371, “Markers for Addiction,” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. A.M.D. is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc. and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies. M.H. and A.C.P. are both employees of CVB, a Sponsor (non-profit) of the study. In the past 3 years, R.C.K. received support for his epidemiological studies from Sanofi Aventis; was a consultant for Johnson & Johnson Wellness and Prevention, Sage Pharmaceuticals, Shire, Takeda; and served on an advisory board for the Johnson & Johnson Services Inc. Lake Nona Life Project. Kessler is a co-owner of DataStat, Inc., a market research firm that carries out healthcare research. H.R.K. is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative (ACTIVE), which in the last three years was supported by AbbVie, Alkermes, Amygdala Neurosciences, Arbor, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. He is also named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. B.M.N. is a member, Scientific Advisory Board of Deep Genomics, a consultant for Camp4 Therapeutics Corporation, Merck & Co. and Avanir Pharmaceuticals, Inc. B.O.R. owns equity in Virtually Better, Inc. that creates virtual reality products. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. In the past 3 years, D.J.S. has received research grants and/or consultancy honoraria from Biocodex, Ludbeck, Servier, and Sun. M.B.S. has in the past three years been a consultant for Actelion, Aptinyx, Bionomics, Dart Neuroscience, Healthcare Management Technologies, Janssen, Neurocrine Biosciences, Oxeia Biopharmaceuticals, Pfizer, and Resilience Therapeutics. R.Y. is a co-inventor of the following patent application: “Genes associated with post-traumatic-stress disorder. European Patent# EP 2334816 B1”. T.W. has acted as scientific advisor to H. Lundbeck A/S. All remaining authors declare no competing interests.

Figures

**Fig. 1**
Manhattan plots from meta-analyses of PTSD GWAS, showing the top variants in six independent genome-wide significant loci. Results are shown for subjects of European (EUA; a) and African ancestry (AFA; c), and for sex-stratified analyses in EUA men (b) and AFA men (d), respectively. Sex-stratified analyses for women were not significant (Supplementary Fig. 4). The red line represents genome-wide significance at P < 5 × 10⁻⁸. Note: rs148757321 and rs142174523 do not remain significant after Bonferroni-adjustment for sex-stratified analyses (at P < 1.67 × 10⁻⁸)

**Fig. 2**
Genetic risk score (PRS) predictions for PTSD. a Using PTSD subjects from the UK Biobank (UKB) as discovery sample, odds ratios (OR) for PTSD per PRS quintile relative to the first quintile show a significant increase in different PGC PTSD target samples. For example, UKB men in the 5th quintile have 40% higher odds to develop PTSD than UKB men in the lowest quintile, when using women from the same population as a training set. b PRS predictions of re-experiencing symptoms in the external replication cohort from the Million Veteran Program (MVP) using the overall PGC2 as discovery sample show a highly significant increase in PTSD re-experiencing symptoms per PRS quintile. Sample sizes in different training and target sets include: UKB women: 6845 PTSD, 64,099 controls; UKB men: 3,544 PTSD, 51,700 controls; UKB: 10,389 PTSD, 115,799 controls; PGC1.5: 10,213 PTSD, 27,445 controls; PGC2: 23,212 PTSD, 151,447 controls; MVP: 146,660 participants with re-experiencing symptoms assessments. Analyses include only subjects of European ancestry

**Fig. 3**
Commonality of genetic correlations between PTSD and other psychiatric disorders and traits with GWAS summary statistics on LD Hub. Psychiatric traits include a PTSD, b MDD, c SCZ, d BPD and e ADHD and their genetic correlations with traits from psychiatric, anthropomorphic, smoking behavior, reproductive, aging, education, autoimmune and cardiometabolic categories. Only traits with at least one significant correlation with the 5 psychiatric disorders are shown. Error bars indicate 95% confidence limits. Solid points indicate significant correlation after Bonferroni correction. The total number of correlations tested were 235 for PTSD, 221 for MDD, 172 for SCZ, 196 for BPD and 219 for ADHD

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References

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International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

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International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

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