International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci
Caroline M. Nievergelt(University of California San Diego), Adam X. Maihofer(University of California San Diego), Torsten Klengel(Harvard University), Elizabeth G. Atkinson(Broad Institute), Chia‐Yen Chen(Broad Institute), Karmel W. Choi(Broad Institute), Jonathan R. I. Coleman(The King's College), Shareefa Dalvie, Laramie E. Duncan(Stanford University), Joel Gelernter(United States Department of Veterans Affairs), Daniel F. Levey(Yale University), Mark W. Logue(VA Boston Healthcare System), Renato Polimanti(Yale University), Allison C. Provost(Cohen Veterans Bioscience), Andrew Ratanatharathorn(Harvard University), Murray B. Stein(University of California San Diego), Katy Torres(University of California San Diego), Allison E. Aiello(University of North Carolina at Chapel Hill), Lynn M. Almli(Emory University), Ananda B. Amstadter, Søren Bo Andersen(Danish Gas Technology Centre (Denmark)), Ole A. Andreassen(University of Oslo), Paul A. Arbisi(Minneapolis VA Health Care System), Allison E. Ashley‐Koch(Duke University), S. Bryn Austin(Brigham and Women's Hospital), Esmina Avdibegović(University Clinical Center Tuzla), Dragan Babić, Marie Bækvad‐Hansen(Statens Serum Institut), Dewleen G. Baker(University of California San Diego), Jean C. Beckham(Duke University), Laura J. Bierut(Washington University in St. Louis), Jonathan I. Bisson(Centre for Mental Health), Marco P. Boks(University Medical Center Utrecht), Elizabeth Bolger(Harvard University), Anders D. Børglum(Aarhus University), Bekh Bradley(Emory University), Megan Brashear(Louisiana State University Health Sciences Center New Orleans), Gerome Breen(The King's College), Richard A. Bryant(UNSW Sydney), Angela C. Bustamante(University of Michigan), Jonas Bybjerg‐Grauholm(Statens Serum Institut), Joseph R. Calabrese(University Hospitals of Cleveland), José Miguel Caldas‐de‐Almeida, Anders M. Dale(University of California San Diego), Mark J. Daly(Massachusetts General Hospital), Nikolaos P. Daskalakis(Harvard University), Jürgen Deckert(Universitätsklinikum Würzburg), Douglas L. Delahanty(Kent State University), Michelle F. Dennis(Duke University), Seth G. Disner(Minneapolis VA Health Care System), Katharina Domschke(University of Freiburg), Alma Džubur Kulenović(University of Sarajevo), Christopher R. Erbes(University of Minnesota), Alexandra Evans, Lindsay A. Farrer(Boston University), Norah C. Feeny(Case Western Reserve University), Janine D. Flory(Icahn School of Medicine at Mount Sinai), David Forbes, Carol E. Franz(University of California San Diego), Sandro Galea(Boston University), Melanie E. Garrett(Duke University), Bizu Gelaye(Harvard University), Elbert Geuze(University Medical Center Utrecht), Charles F. Gillespie(Emory University), Aferdita Goci Uka(University Clinical Center of Kosovo), Scott D. Gordon(QIMR Berghofer Medical Research Institute), Guia Guffanti(Harvard University), Rasha Hammamieh(United States Army Medical Research and Development Command), Supriya Harnal(Broad Institute), Michael A. Hauser(Duke University), Andrew C. Heath(Washington University in St. Louis), Sian Hemmings(Western Cape Department of Health), David M. Hougaard(Statens Serum Institut), Miro Jakovljević, Marti Jett(United States Army Medical Research and Development Command), Eric O. Johnson(RTI International), Ian Jones, Tanja Jovanović(Emory University), Xuejun Qin(Duke University), Angela G. Junglen(Kent State University), Karen‐Inge Karstoft(University of Copenhagen), Milissa L. Kaufman(Harvard University), Ronald C. Kessler(Harvard University), Alaptagin Khan(Harvard University), Nathan A. Kimbrel(Duke University), Anthony P. King(University of Michigan), Nastassja Koen, Henry R. Kranzler(University of Pennsylvania), William S. Kremen(University of California San Diego), Bruce R. Lawford(Queensland University of Technology), Lauren A. M. Lebois(Harvard University), Catrin E. Lewis, Sarah D. Linnstaedt(University of North Carolina Health Care), Adriana Lori(Emory University), Božo Lugonja, Jurjen J. Luykx(University Medical Center Utrecht), Michael J. Lyons(Boston University), Jessica L. Maples‐Keller(Emory University), Charles R. Marmar(New York University), Alicia R. Martin(Broad Institute), Nicholas G. Martin(QIMR Berghofer Medical Research Institute), Douglas Maurer(United States Army Medical Command), Matig Mavissakalian(University Hospitals of Cleveland), Alexander C. McFarlane(The University of Adelaide), Regina E. McGlinchey(VA Boston Healthcare System), Katie A. McLaughlin(Harvard University), Samuel A. McLean(University of North Carolina Health Care), Sarah McLeay(Gallipoli Medical Research Foundation), Divya Mehta(Queensland University of Technology), William Milberg(VA Boston Healthcare System), Mark W. Miller(VA Boston Healthcare System), Rajendra A. Morey(Duke University), C. Phillip Morris(Queensland University of Technology), Ole Mors(Aarhus University Hospital), Preben Bo Mortensen(Aarhus University), Benjamin M. Neale(Broad Institute), Elliot C. Nelson(Washington University in St. Louis), Merete Nordentoft(Mental Health Services), Sonya B. Norman(University of California San Diego), Meaghan O’Donnell, Holly K. Orcutt(Northern Illinois University), Matthew S. Panizzon(University of California San Diego), Edward Peters(Louisiana State University Health Sciences Center New Orleans), Alan L. Peterson(The University of Texas at San Antonio Health Science Center), Matthew Peverill(University of Washington), Robert H. Pietrzak(United States Department of Veterans Affairs), Melissa A. Polusny(University of Minnesota), John P. Rice(Washington University in St. Louis), Stephan Ripke(Broad Institute), Victoria B. Risbrough(University of California San Diego), Andrea L. Roberts(Harvard University), Alex O. Rothbaum(Case Western Reserve University), Barbara O. Rothbaum(Emory University), Peter Roy‐Byrne(University of Washington), Ken Ruggiero(Medical University of South Carolina), Ariane L. Rung(Louisiana State University Health Sciences Center New Orleans), Bart P. F. Rutten, Nancy L. Saccone(Washington University in St. Louis), Sixto E. Sánchez(Peruvian University of Applied Sciences), Dick Schijven(University Medical Center Utrecht), Soraya Seedat(Western Cape Department of Health), Antonia V. Seligowski(Harvard University), Julia S. Seng(University of Michigan), Christina M. Sheerin, Derrick Silove, Alicia K. Smith(Emory University), Jordan W. Smoller(Broad Institute), Scott R. Sponheim(University of Minnesota), Dan J. Stein, Jennifer S. Stevens(Emory University), Jennifer A. Sumner(Columbia University Irving Medical Center), Martin H. Teicher(Harvard University), Wesley K. Thompson(Oslo University Hospital), Edward Trapido(Louisiana State University Health Sciences Center New Orleans), Monica Uddin(University of South Florida), Robert J. Ursano(Uniformed Services University of the Health Sciences), Leigh L. van den Heuvel(Western Cape Department of Health), Miranda Van Hooff(The University of Adelaide), Eric Vermetten(Leiden University Medical Center), Christiaan H. Vinkers(Amsterdam Neuroscience), Joanne Voisey(Queensland University of Technology), Yunpeng Wang(Oslo University Hospital), Zhewu Wang(Medical University of South Carolina), Thomas Werge(University of Copenhagen), Michelle A. Williams(Harvard University), Douglas E. Williamson(Duke University), Sherry Winternitz(Harvard University), Christiane Wolf(Universitätsklinikum Würzburg), Erika J. Wolf(VA Boston Healthcare System), Jonathan D. Wolff(McLean Hospital), Rachel Yehuda(James J. Peters VA Medical Center), Ross McD. Young(Queensland University of Technology), Keith A. Young(Baylor Scott & White Medical Center - Temple), Hongyu Zhao(Yale University), Lori A. Zoellner(University of Washington), Israel Liberzon(University of Michigan), Kerry J. Ressler(Harvard University), Magali Haas(Cohen Veterans Bioscience), Karestan C. Koenen(Broad Institute)
Cited by 677Open Access
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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