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Nat Commun. 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.

Nievergelt CM1,2,3, Maihofer AX4,5,6, Klengel T7,8,9, Atkinson EG10,11, Chen CY10,11,12, Choi KW10,13,14, Coleman JRI15,16, Dalvie S17, Duncan LE18, Gelernter J19,20,21, Levey DF21,22, Logue MW23, Polimanti R21,22, Provost AC24, Ratanatharathorn A14, Stein MB4,25,26, Torres K4,5,6, Aiello AE27, Almli LM28, Amstadter AB29, Andersen SB30, Andreassen OA31, Arbisi PA32, Ashley-Koch AE33, Austin SB7,34,35,36, Avdibegovic E37, Babić D38, Bækvad-Hansen M39,40, Baker DG4,5,26, Beckham JC41,42,43, Bierut LJ44, Bisson JI45, Boks MP46, Bolger EA7,8, Børglum AD40,47,48, Bradley B28,49, Brashear M50, Breen G15,16, Bryant RA51, Bustamante AC52, Bybjerg-Grauholm J39,40, Calabrese JR53, Caldas-de-Almeida JM54, Dale AM55, Daly MJ12, Daskalakis NP7,8,24,56, Deckert J57, Delahanty DL58,59, Dennis MF41,42,43, Disner SG60, Domschke K61,62, Dzubur-Kulenovic A63, Erbes CR64,65, Evans A66, Farrer LA67, Feeny NC68, Flory JD56, Forbes D69, Franz CE4, Galea S70, Garrett ME42, Gelaye B14, Geuze E71,72, Gillespie C28, Uka AG73, Gordon SD74, Guffanti G7,8, Hammamieh R75, Harnal S10, Hauser MA42, Heath AC76, Hemmings SMJ77, Hougaard DM39,40, Jakovljevic M78, Jett M75, Johnson EO79, Jones I66, Jovanovic T28, Qin XJ33, Junglen AG58, Karstoft KI30,80, Kaufman ML7,8, Kessler RC7, Khan A8,81, Kimbrel NA33,41,43, King AP82, Koen N17, Kranzler HR83,84, Kremen WS4,5, Lawford BR85,86, Lebois LAM7,8, Lewis CE66, Linnstaedt SD87, Lori A88, Lugonja B66, Luykx JJ46,72, Lyons MJ89, Maples-Keller J28, Marmar C90, Martin AR10,11, Martin NG74, Maurer D91, Mavissakalian MR53, McFarlane A92, McGlinchey RE93, McLaughlin KA94, McLean SA87,95, McLeay S96, Mehta D85,97, Milberg WP93, Miller MW23, Morey RA33, Morris CP85,86, Mors O40,98, Mortensen PB40,47,99,100, Neale BM10,11, Nelson EC44, Nordentoft M40,101, Norman SB4,102,103, O'Donnell M69, Orcutt HK104, Panizzon MS4, Peters ES50, Peterson AL105, Peverill M106, Pietrzak RH22,107, Polusny MA64,108,109, Rice JP44, Ripke S10,12,110, Risbrough VB4,5,6, Roberts AL111, Rothbaum AO68, Rothbaum BO28, Roy-Byrne P106, Ruggiero K112, Rung A50, Rutten BPF113, Saccone NL44, Sanchez SE114, Schijven D46,72, Seedat S77, Seligowski AV7,8, Seng JS115, Sheerin CM29, Silove D116, Smith AK28,88, Smoller JW10,11,13, Sponheim SR32,64, Stein DJ17, Stevens JS28, Sumner JA117, Teicher MH7,8, Thompson WK4,40,118,119, Trapido E50, Uddin M120, Ursano RJ121, van den Heuvel LL77, Van Hooff M92, Vermetten E90,122,123,124, Vinkers CH125,126, Voisey J85,86, Wang Y40,118,119, Wang Z127,128, Werge T40,118,129, Williams MA14, Williamson DE41,42, Winternitz S7,8, Wolf C57, Wolf EJ23, Wolff JD8, Yehuda R56,130, Young RM85,97, Young KA131,132, Zhao H133, Zoellner LA134, Liberzon I82, Ressler KJ7,8,28, Haas M24, Koenen KC10,12,135.

Author information

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.

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.

PMID:
31594949
DOI:
10.1038/s41467-019-12576-w
Free PMC Article

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