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

Caroline M. Nievergelt (), Adam X. Maihofer, Torsten Klengel, Elizabeth G. Atkinson, Chia-Yen Chen, Karmel W. Choi, Jonathan R. I. Coleman, Shareefa Dalvie, Laramie E. Duncan, Joel Gelernter, Daniel F. Levey, Mark W. Logue, Renato Polimanti, Allison C. Provost, Andrew Ratanatharathorn, Murray B. Stein, Katy Torres, Allison E. Aiello, Lynn M. Almli, Ananda B. Amstadter, Søren B. Andersen, Ole A. Andreassen, Paul A. Arbisi, Allison E. Ashley-Koch, S. Bryn Austin, Esmina Avdibegovic, Dragan Babić, Marie Bækvad-Hansen, Dewleen G. Baker, Jean C. Beckham, Laura J. Bierut, Jonathan I. Bisson, Marco P. Boks, Elizabeth A. Bolger, Anders D. Børglum, Bekh Bradley, Megan Brashear, Gerome Breen, Richard A. Bryant, Angela C. Bustamante, Jonas Bybjerg-Grauholm, Joseph R. Calabrese, José M. Caldas- de- Almeida, Anders M. Dale, Mark J. Daly, Nikolaos P. Daskalakis, Jürgen Deckert, Douglas L. Delahanty, Michelle F. Dennis, Seth G. Disner, Katharina Domschke, Alma Dzubur-Kulenovic, Christopher R. Erbes, Alexandra Evans, Lindsay A. Farrer, Norah C. Feeny, Janine D. Flory, David Forbes, Carol E. Franz, Sandro Galea, Melanie E. Garrett, Bizu Gelaye, Elbert Geuze, Charles Gillespie, Aferdita Goci Uka, Scott D. Gordon, Guia Guffanti, Rasha Hammamieh, Supriya Harnal, Michael A. Hauser, Andrew C. Heath, Sian M. J. Hemmings, David Michael Hougaard, Miro Jakovljevic, Marti Jett, Eric Otto Johnson, Ian Jones, Tanja Jovanovic, Xue-Jun Qin, Angela G. Junglen, Karen-Inge Karstoft, Milissa L. Kaufman, Ronald C. Kessler, Alaptagin Khan, Nathan A. Kimbrel, Anthony P. King, Nastassja Koen, Henry R. Kranzler, William S. Kremen, Bruce R. Lawford, Lauren A. M. Lebois, Catrin E. Lewis, Sarah D. Linnstaedt, Adriana Lori, Bozo Lugonja, Jurjen J. Luykx, Michael J. Lyons, Jessica Maples-Keller, Charles Marmar, Alicia R. Martin, Nicholas G. Martin, Douglas Maurer, Matig R. Mavissakalian, Alexander McFarlane, Regina E. McGlinchey, Katie A. McLaughlin, Samuel A. McLean, Sarah McLeay, Divya Mehta, William P. Milberg, Mark W. Miller, Rajendra A. Morey, Charles Phillip Morris, Ole Mors, Preben B. Mortensen, Benjamin M. Neale, Elliot C. Nelson, Merete Nordentoft, Sonya B. Norman, Meaghan O’Donnell, Holly K. Orcutt, Matthew S. Panizzon, Edward S. Peters, Alan L. Peterson, Matthew Peverill, Robert H. Pietrzak, Melissa A. Polusny, John P. Rice, Stephan Ripke, Victoria B. Risbrough, Andrea L. Roberts, Alex O. Rothbaum, Barbara O. Rothbaum, Peter Roy-Byrne, Ken Ruggiero, Ariane Rung, Bart P. F. Rutten, Nancy L. Saccone, Sixto E. Sanchez, Dick Schijven, Soraya Seedat, Antonia V. Seligowski, Julia S. Seng, Christina M. Sheerin, Derrick Silove, Alicia K. Smith, Jordan W. Smoller, Scott R. Sponheim, Dan J. Stein, Jennifer S. Stevens, Jennifer A. Sumner, Martin H. Teicher, Wesley K. Thompson, Edward Trapido, Monica Uddin, Robert J. Ursano, Leigh Luella Heuvel, Miranda Hooff, Eric Vermetten, Christiaan H. Vinkers, Joanne Voisey, Yunpeng Wang, Zhewu Wang, Thomas Werge, Michelle A. Williams, Douglas E. Williamson, Sherry Winternitz, Christiane Wolf, Erika J. Wolf, Jonathan D. Wolff, Rachel Yehuda, Ross McD. Young, Keith A. Young, Hongyu Zhao, Lori A. Zoellner, Israel Liberzon, Kerry J. Ressler, Magali Haas and Karestan C. Koenen
Additional contact information
Caroline M. Nievergelt: University of California San Diego, Department of Psychiatry
Adam X. Maihofer: University of California San Diego, Department of Psychiatry
Torsten Klengel: Harvard Medical School, Department of Psychiatry
Elizabeth G. Atkinson: Stanley Center for Psychiatric Research
Chia-Yen Chen: Stanley Center for Psychiatric Research
Karmel W. Choi: Stanley Center for Psychiatric Research
Jonathan R. I. Coleman: Institute of Psychiatry, Psychology and Neuroscience
Shareefa Dalvie: University of Cape Town, SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, Cape Town
Laramie E. Duncan: Stanford University, Department of Psychiatry and Behavioral Sciences
Joel Gelernter: US Department of Veterans Affairs, Department of Psychiatry
Daniel F. Levey: VA Connecticut Healthcare Center
Mark W. Logue: National Center for PTSD
Renato Polimanti: VA Connecticut Healthcare Center
Allison C. Provost: Cohen Veterans Bioscience
Andrew Ratanatharathorn: Harvard T.H. Chan School of Public Health, Department of Epidemiology
Murray B. Stein: University of California San Diego, Department of Psychiatry
Katy Torres: University of California San Diego, Department of Psychiatry
Allison E. Aiello: Department of Epidemiology
Lynn M. Almli: Emory University, Department of Psychiatry and Behavioral Sciences
Ananda B. Amstadter: Department of Psychiatry
Søren B. Andersen: Research and Knowledge Centre
Ole A. Andreassen: University of Oslo, Institute of Clinical Medicine
Paul A. Arbisi: Mental Health Service Line
Allison E. Ashley-Koch: Duke University, Duke Molecular Physiology Institute
S. Bryn Austin: Harvard Medical School, Department of Psychiatry
Esmina Avdibegovic: University Clinical Center of Tuzla, Department of Psychiatry
Dragan Babić: University Clinical Center of Mostar, Department of Psychiatry
Marie Bækvad-Hansen: Statens Serum Institut, Department for Congenital Disorders
Dewleen G. Baker: University of California San Diego, Department of Psychiatry
Jean C. Beckham: Durham VA Medical Center, Research
Laura J. Bierut: Washington University in Saint Louis School of Medicine, Department of Psychiatry
Jonathan I. Bisson: Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics
Marco P. Boks: UMC Utrecht Brain Center Rudolf Magnus, Department of Translational Neuroscience, Utrecht
Elizabeth A. Bolger: Harvard Medical School, Department of Psychiatry
Anders D. Børglum: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Bekh Bradley: Emory University, Department of Psychiatry and Behavioral Sciences
Megan Brashear: Louisiana State University Health Sciences Center, School of Public Health and Department of Epidemiology
Gerome Breen: Institute of Psychiatry, Psychology and Neuroscience
Richard A. Bryant: University of New South Wales, Department of Psychology
Angela C. Bustamante: University of Michigan Medical School, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine
Jonas Bybjerg-Grauholm: Statens Serum Institut, Department for Congenital Disorders
Joseph R. Calabrese: University Hospitals, Department of Psychiatry
José M. Caldas- de- Almeida: Lisbon Institute of Global Mental Health
Anders M. Dale: University of California San Diego, Department of Radiology, Department of Neurosciences
Mark J. Daly: Psychiatric and Neurodevelopmental Genetics Unit (PNGU)
Nikolaos P. Daskalakis: Harvard Medical School, Department of Psychiatry
Jürgen Deckert: University Hospital of Würzburg, Center of Mental Health, Psychiatry, Psychosomatics and Psychotherapy
Douglas L. Delahanty: Kent State University, Department of Psychological Sciences
Michelle F. Dennis: Durham VA Medical Center, Research
Seth G. Disner: Research Service Line
Katharina Domschke: Department of Psychiatry and Psychotherapy
Alma Dzubur-Kulenovic: University Clinical Center of Sarajevo, Department of Psychiatry
Christopher R. Erbes: University of Minnesota, Department of Psychiatry
Alexandra Evans: Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, Cardiff
Lindsay A. Farrer: Boston University School of Medicine, Department of Medicine
Norah C. Feeny: Case Western Reserve University, Department of Psychological Sciences
Janine D. Flory: Icahn School of Medicine at Mount Sinai, Department of Psychiatry
David Forbes: University of Melbourne, Department of Psychiatry, Melbourne
Carol E. Franz: University of California San Diego, Department of Psychiatry
Sandro Galea: Boston University, Department of Psychological and Brain Sciences
Melanie E. Garrett: Duke University, Department of Psychiatry and Behavioral Sciences
Bizu Gelaye: Harvard T.H. Chan School of Public Health, Department of Epidemiology
Elbert Geuze: Brain Research and Innovation Centre, Utrecht
Charles Gillespie: Emory University, Department of Psychiatry and Behavioral Sciences
Aferdita Goci Uka: University Clinical Centre of Kosovo, Department of Psychiatry, Prishtina
Scott D. Gordon: Department of Genetics and Computational Biology
Guia Guffanti: Harvard Medical School, Department of Psychiatry
Rasha Hammamieh: USACEHR
Supriya Harnal: Stanley Center for Psychiatric Research
Michael A. Hauser: Duke University, Department of Psychiatry and Behavioral Sciences
Andrew C. Heath: Washington University in Saint Louis School of Medicine, Department of Genetics
Sian M. J. Hemmings: Stellenbosch University Faculty of Medicine and Health Sciences, Department of Psychiatry, Cape Town
David Michael Hougaard: Statens Serum Institut, Department for Congenital Disorders
Miro Jakovljevic: University Hospital Center of Zagreb, Department of Psychiatry
Marti Jett: USACEHR
Eric Otto Johnson: RTI International, Behavioral Health and Criminal Justice Division
Ian Jones: Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, Cardiff
Tanja Jovanovic: Emory University, Department of Psychiatry and Behavioral Sciences
Xue-Jun Qin: Duke University, Duke Molecular Physiology Institute
Angela G. Junglen: Kent State University, Department of Psychological Sciences
Karen-Inge Karstoft: Research and Knowledge Centre
Milissa L. Kaufman: Harvard Medical School, Department of Psychiatry
Ronald C. Kessler: Harvard Medical School, Department of Psychiatry
Alaptagin Khan: McLean Hospital
Nathan A. Kimbrel: Duke University, Duke Molecular Physiology Institute
Anthony P. King: University of Michigan Medical School, Department of Psychiatry
Nastassja Koen: University of Cape Town, SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, Cape Town
Henry R. Kranzler: University of Pennsylvania Perelman School of Medicine, Department of Psychiatry
William S. Kremen: University of California San Diego, Department of Psychiatry
Bruce R. Lawford: Queensland University of Technology, Institute of Health and Biomedical Innovation, Kelvin Grove
Lauren A. M. Lebois: Harvard Medical School, Department of Psychiatry
Catrin E. Lewis: Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, Cardiff
Sarah D. Linnstaedt: Department of Anesthesiology
Adriana Lori: Emory University, Department of Gynecology and Obstetrics
Bozo Lugonja: Cardiff University, National Centre for Mental Health, MRC Centre for Psychiatric Genetics and Genomics, Cardiff
Jurjen J. Luykx: UMC Utrecht Brain Center Rudolf Magnus, Department of Translational Neuroscience, Utrecht
Michael J. Lyons: Boston University, Dean’s Office
Jessica Maples-Keller: Emory University, Department of Psychiatry and Behavioral Sciences
Charles Marmar: New York University School of Medicine, Department of Psychiatry
Alicia R. Martin: Stanley Center for Psychiatric Research
Nicholas G. Martin: Department of Genetics and Computational Biology
Douglas Maurer: United States Army, Command
Matig R. Mavissakalian: University Hospitals, Department of Psychiatry
Alexander McFarlane: University of Adelaide, Department of Psychiatry, Adelaide
Regina E. McGlinchey: VA Boston Health Care System, GRECC/TRACTS
Katie A. McLaughlin: Harvard University, Department of Psychology
Samuel A. McLean: Department of Anesthesiology
Sarah McLeay: Gallipoli Medical Research Institute, PTSD Initiative, Greenslopes
Divya Mehta: Queensland University of Technology, Institute of Health and Biomedical Innovation, Kelvin Grove
William P. Milberg: VA Boston Health Care System, GRECC/TRACTS
Mark W. Miller: National Center for PTSD
Rajendra A. Morey: Duke University, Duke Molecular Physiology Institute
Charles Phillip Morris: Queensland University of Technology, Institute of Health and Biomedical Innovation, Kelvin Grove
Ole Mors: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Preben B. Mortensen: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Benjamin M. Neale: Stanley Center for Psychiatric Research
Elliot C. Nelson: Washington University in Saint Louis School of Medicine, Department of Psychiatry
Merete Nordentoft: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Sonya B. Norman: University of California San Diego, Department of Psychiatry
Meaghan O’Donnell: University of Melbourne, Department of Psychiatry, Melbourne
Holly K. Orcutt: Northern Illinois University, Department of Psychology
Matthew S. Panizzon: University of California San Diego, Department of Psychiatry
Edward S. Peters: Louisiana State University Health Sciences Center, School of Public Health and Department of Epidemiology
Alan L. Peterson: University of Texas Health Science Center at San Antonio, Department of Psychiatry
Matthew Peverill: University of Washington, Department of Psychology
Robert H. Pietrzak: Yale University School of Medicine, Department of Psychiatry
Melissa A. Polusny: University of Minnesota, Department of Psychiatry
John P. Rice: Washington University in Saint Louis School of Medicine, Department of Psychiatry
Stephan Ripke: Stanley Center for Psychiatric Research
Victoria B. Risbrough: University of California San Diego, Department of Psychiatry
Andrea L. Roberts: Department of Environmental Health
Alex O. Rothbaum: Case Western Reserve University, Department of Psychological Sciences
Barbara O. Rothbaum: Emory University, Department of Psychiatry and Behavioral Sciences
Peter Roy-Byrne: University of Washington, Department of Psychology
Ken Ruggiero: Medical University of South Carolina, Department of Nursing and Department of Psychiatry
Ariane Rung: Louisiana State University Health Sciences Center, School of Public Health and Department of Epidemiology
Bart P. F. Rutten: Maastricht Universitair Medisch Centrum, School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht
Nancy L. Saccone: Washington University in Saint Louis School of Medicine, Department of Psychiatry
Sixto E. Sanchez: Universidad Peruana de Ciencias Aplicadas Facultad de Ciencias de la Salud, Department of Medicine, Lima
Dick Schijven: UMC Utrecht Brain Center Rudolf Magnus, Department of Translational Neuroscience, Utrecht
Soraya Seedat: Stellenbosch University Faculty of Medicine and Health Sciences, Department of Psychiatry, Cape Town
Antonia V. Seligowski: Harvard Medical School, Department of Psychiatry
Julia S. Seng: University of Michigan, School of Nursing
Christina M. Sheerin: Department of Psychiatry
Derrick Silove: University of New South Wales, Department of Psychiatry, Sydney
Alicia K. Smith: Emory University, Department of Psychiatry and Behavioral Sciences
Jordan W. Smoller: Stanley Center for Psychiatric Research
Scott R. Sponheim: Mental Health Service Line
Dan J. Stein: University of Cape Town, SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, Cape Town
Jennifer S. Stevens: Emory University, Department of Psychiatry and Behavioral Sciences
Jennifer A. Sumner: Columbia University Medical Center, Department of Medicine
Martin H. Teicher: Harvard Medical School, Department of Psychiatry
Wesley K. Thompson: University of California San Diego, Department of Psychiatry
Edward Trapido: Louisiana State University Health Sciences Center, School of Public Health and Department of Epidemiology
Monica Uddin: University of South Florida College of Public Health, Genomics Program
Robert J. Ursano: Uniformed Services University, Department of Psychiatry
Leigh Luella Heuvel: Stellenbosch University Faculty of Medicine and Health Sciences, Department of Psychiatry, Cape Town
Miranda Hooff: University of Adelaide, Department of Psychiatry, Adelaide
Eric Vermetten: New York University School of Medicine, Department of Psychiatry
Christiaan H. Vinkers: Department of Anatomy and Neurosciences, Amsterdam
Joanne Voisey: Queensland University of Technology, Institute of Health and Biomedical Innovation, Kelvin Grove
Yunpeng Wang: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Zhewu Wang: Department of Mental Health
Thomas Werge: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Michelle A. Williams: Harvard T.H. Chan School of Public Health, Department of Epidemiology
Douglas E. Williamson: Durham VA Medical Center, Research
Sherry Winternitz: Harvard Medical School, Department of Psychiatry
Christiane Wolf: University Hospital of Würzburg, Center of Mental Health, Psychiatry, Psychosomatics and Psychotherapy
Erika J. Wolf: National Center for PTSD
Jonathan D. Wolff: McLean Hospital
Rachel Yehuda: Icahn School of Medicine at Mount Sinai, Department of Psychiatry
Ross McD. Young: Queensland University of Technology, Institute of Health and Biomedical Innovation, Kelvin Grove
Keith A. Young: Department of Psychiatry
Hongyu Zhao: Yale University, Department of Biostatistics
Lori A. Zoellner: University of Washington, Department of Psychiatry and Behavioral Sciences
Israel Liberzon: University of Michigan Medical School, Department of Psychiatry
Kerry J. Ressler: Harvard Medical School, Department of Psychiatry
Magali Haas: Cohen Veterans Bioscience
Karestan C. Koenen: Stanley Center for Psychiatric Research

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12576-w

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