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. 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; Sren B. Andersen; Ole A. Andreassen; Paul A. Arbisi; Allison E. Ashley-Koch; S. Bryn Austin; Esmina Avdibegovic; Dragan Babic; Marie Baekvad-Hansen; Dewleen G. Baker; Jean C. Beckham; Laura J. Bierut; Jonathan Bisson; Marco P. Boks; Elizabeth A. Bolger; Anders D. Brglum; Bekh Bradley; Megan Brashear; Gerome Breen; Richard A. Bryant; Angela C. Bustamante; Jonas Bybjerg-Grauholm; Joseph R. Calabrese; Jose M. Caldas-de-Almeida; Anders M. Dale; Mark J. Daly; Nikolaos P. Daskalakis; Juergen 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 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 van den Heuvel; Miranda Van 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; Karestan C. Koenen

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^*, Adam X. Maihofer, Torsten Klengel, Elizabeth G. Atkinson, Chia-Yen Chen, Karmel W. Choi, Jonathan R. 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. AmstadterSren B. Andersen, Ole A. Andreassen, Paul A. Arbisi, Allison E. Ashley-Koch, S. Bryn Austin, Esmina Avdibegovic, Dragan Babic, Marie Baekvad-Hansen, Dewleen G. Baker, Jean C. Beckham, Laura J. Bierut, Jonathan Bisson, Marco P. Boks, Elizabeth A. Bolger, Anders D. Brglum, Bekh Bradley, Megan Brashear, Gerome Breen, Richard A. Bryant, Angela C. Bustamante, Jonas Bybjerg-Grauholm, Joseph R. Calabrese, Jose M. Caldas-de-Almeida, Anders M. Dale, Mark J. Daly, Nikolaos P. Daskalakis, Juergen 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 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 van den Heuvel, Miranda Van 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, Karestan C. Koenen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	4558
Number of pages	16
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-12576-w
Publication status	Published - 8 Oct 2019

Keywords

POSTTRAUMATIC-STRESS-DISORDER
HUMAN DEMOGRAPHIC HISTORY
LD SCORE REGRESSION
PARKINSON DISEASE
SNP HERITABILITY
TRAUMA
EFFICIENT
PREVENTION
PROFILES
SYMPTOMS

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Cite this

Nievergelt, C. M., Maihofer, A. X., Klengel, T., Atkinson, E. G., Chen, C.-Y., Choi, K. W., Coleman, J. R., Dalvie, S., Duncan, L. E., Gelernter, J., Levey, D. F., Logue, M. W., Polimanti, R., Provost, A. C., Ratanatharathorn, A., Stein, M. B., Torres, K., Aiello, A. E., Almli, L. M., ... Koenen, K. C. (2019). International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nature Communications, 10, Article 4558. https://doi.org/10.1038/s41467-019-12576-w

@article{cb1c480fbb384c34812a9afbd42ef111,

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

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.",

keywords = "POSTTRAUMATIC-STRESS-DISORDER, HUMAN DEMOGRAPHIC HISTORY, LD SCORE REGRESSION, PARKINSON DISEASE, SNP HERITABILITY, TRAUMA, EFFICIENT, PREVENTION, PROFILES, SYMPTOMS",

author = "Nievergelt, {Caroline M.} and Maihofer, {Adam X.} and Torsten Klengel and Atkinson, {Elizabeth G.} and Chia-Yen Chen and Choi, {Karmel W.} and Coleman, {Jonathan R.} and Shareefa Dalvie and Duncan, {Laramie E.} and Joel Gelernter and Levey, {Daniel F.} and Logue, {Mark W.} and Renato Polimanti and Provost, {Allison C.} and Andrew Ratanatharathorn and Stein, {Murray B.} and Katy Torres and Aiello, {Allison E.} and Almli, {Lynn M.} and Amstadter, {Ananda B.} and Andersen, {Sren B.} and Andreassen, {Ole A.} and Arbisi, {Paul A.} and Ashley-Koch, {Allison E.} and Austin, {S. Bryn} and Esmina Avdibegovic and Dragan Babic and Marie Baekvad-Hansen and Baker, {Dewleen G.} and Beckham, {Jean C.} and Bierut, {Laura J.} and Jonathan Bisson and Boks, {Marco P.} and Bolger, {Elizabeth A.} and Brglum, {Anders D.} and Bekh Bradley and Megan Brashear and Gerome Breen and Bryant, {Richard A.} and Bustamante, {Angela C.} and Jonas Bybjerg-Grauholm and Calabrese, {Joseph R.} and Caldas-de-Almeida, {Jose M.} and Dale, {Anders M.} and Daly, {Mark J.} and Daskalakis, {Nikolaos P.} and Juergen Deckert and Delahanty, {Douglas L.} and Dennis, {Michelle F.} and Disner, {Seth G.} and Katharina Domschke and Alma Dzubur-Kulenovic and Erbes, {Christopher R.} and Alexandra Evans and Farrer, {Lindsay A.} and Feeny, {Norah C.} and Flory, {Janine D.} and David Forbes and Franz, {Carol E.} and Sandro Galea and Garrett, {Melanie E.} and Bizu Gelaye and Elbert Geuze and Charles Gillespie and Uka, {Aferdita Goci} and Gordon, {Scott D.} and Guia Guffanti and Rasha Hammamieh and Supriya Harnal and Hauser, {Michael A.} and Heath, {Andrew C.} and Hemmings, {Sian M. J.} and Hougaard, {David Michael} and Miro Jakovljevic and Marti Jett and Johnson, {Eric Otto} and Ian Jones and Tanja Jovanovic and Xue-Jun Qin and Junglen, {Angela G.} and Karen-Inge Karstoft and Kaufman, {Milissa L.} and Kessler, {Ronald C.} and Alaptagin Khan and Kimbrel, {Nathan A.} and King, {Anthony P.} and Nastassja Koen and Kranzler, {Henry R.} and Kremen, {William S.} and Lawford, {Bruce R.} and Lebois, {Lauren A. M.} and Lewis, {Catrin E.} and Linnstaedt, {Sarah D.} and Adriana Lori and Bozo Lugonja and Luykx, {Jurjen J.} and Lyons, {Michael J.} and Jessica Maples-Keller and Charles Marmar and Martin, {Alicia R.} and Martin, {Nicholas G.} and Douglas Maurer and Mavissakalian, {Matig R.} and Alexander McFarlane and McGlinchey, {Regina E.} and McLaughlin, {Katie A.} and McLean, {Samuel A.} and Sarah McLeay and Divya Mehta and Milberg, {William P.} and Miller, {Mark W.} and Morey, {Rajendra A.} and Morris, {Charles Phillip} and Ole Mors and Mortensen, {Preben B.} and Neale, {Benjamin M.} and Nelson, {Elliot C.} and Merete Nordentoft and Norman, {Sonya B.} and Meaghan O'Donnell and Orcutt, {Holly K.} and Panizzon, {Matthew S.} and Peters, {Edward S.} and Peterson, {Alan L.} and Matthew Peverill and Pietrzak, {Robert H.} and Polusny, {Melissa A.} and Rice, {John P.} and Stephan Ripke and Risbrough, {Victoria B.} and Roberts, {Andrea L.} and Rothbaum, {Alex O.} and Rothbaum, {Barbara O.} and Peter Roy-Byrne and Ken Ruggiero and Ariane Rung and Rutten, {Bart P. F.} and Saccone, {Nancy L.} and Sanchez, {Sixto E.} and Dick Schijven and Soraya Seedat and Antonia Seligowski and Seng, {Julia S.} and Sheerin, {Christina M.} and Derrick Silove and Smith, {Alicia K.} and Smoller, {Jordan W.} and Sponheim, {Scott R.} and Stein, {Dan J.} and Stevens, {Jennifer S.} and Sumner, {Jennifer A.} and Teicher, {Martin H.} and Thompson, {Wesley K.} and Edward Trapido and Monica Uddin and Ursano, {Robert J.} and {van den Heuvel}, {Leigh Luella} and {Van Hooff}, Miranda and Eric Vermetten and Vinkers, {Christiaan H.} and Joanne Voisey and Yunpeng Wang and Zhewu Wang and Thomas Werge and Williams, {Michelle A.} and Williamson, {Douglas E.} and Sherry Winternitz and Christiane Wolf and Wolf, {Erika J.} and Wolff, {Jonathan D.} and Rachel Yehuda and Young, {Ross McD} and Young, {Keith A.} and Hongyu Zhao and Zoellner, {Lori A.} and Israel Liberzon and Ressler, {Kerry J.} and Magali Haas and Koenen, {Karestan C.}",

note = "Funding Information: 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 (nonprofit) 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{\textquoteright}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 Bio-pharmaceuticals, 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. Funding Information: This work was funded by Cohen Veterans Bioscience, the NIMH/U.S. Army Medical Research and Materiel Command Grant R01MH106595 to C.M.N., I.L., K.J.R. and K.C.K., One Mind, and supported by 5U01MH109539 to the Psychiatric Genomics Consortium. Statistical Analysis were carried out on the NL Genetic Cluster computer (URL) hosted by SURFsara. Genotyping of samples was supported in part through the Stanley Center for Psychiatric Genetics at the Broad Institute of MIT and Harvard. This research has been conducted using the UK biobank resource under application number 16577. This work would not have been possible without the contributions of the investigators who comprise the PGC-PTSD working group, and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. Full acknowledgements are in the Supplementary Note 2. Publisher Copyright: {\textcopyright} 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2019",

month = oct,

day = "8",

doi = "10.1038/s41467-019-12576-w",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Nievergelt, CM, Maihofer, AX, Klengel, T, Atkinson, EG, Chen, C-Y, Choi, KW, Coleman, JR, Dalvie, S, Duncan, LE, Gelernter, J, Levey, DF, Logue, MW, Polimanti, R, Provost, AC, Ratanatharathorn, A, Stein, MB, Torres, K, Aiello, AE, Almli, LM, Amstadter, AB, Andersen, SB, Andreassen, OA, Arbisi, PA, Ashley-Koch, AE, Austin, SB, Avdibegovic, E, Babic, D, Baekvad-Hansen, M, Baker, DG, Beckham, JC, Bierut, LJ, Bisson, J, Boks, MP, Bolger, EA, Brglum, AD, Bradley, B, Brashear, M, Breen, G, Bryant, RA, Bustamante, AC, Bybjerg-Grauholm, J, Calabrese, JR, Caldas-de-Almeida, JM, Dale, AM, Daly, MJ, Daskalakis, NP, Deckert, J, Delahanty, DL, Dennis, MF, Disner, SG, Domschke, K, Dzubur-Kulenovic, A, Erbes, CR, Evans, A, Farrer, LA, Feeny, NC, Flory, JD, Forbes, D, Franz, CE, Galea, S, Garrett, ME, Gelaye, B, Geuze, E, Gillespie, C, Uka, AG, Gordon, SD, Guffanti, G, Hammamieh, R, Harnal, S, Hauser, MA, Heath, AC, Hemmings, SMJ, Hougaard, DM, Jakovljevic, M, Jett, M, Johnson, EO, Jones, I, Jovanovic, T, Qin, X-J, Junglen, AG, Karstoft, K-I, Kaufman, ML, Kessler, RC, Khan, A, Kimbrel, NA, King, AP, Koen, N, Kranzler, HR, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, CE, Linnstaedt, SD, Lori, A, Lugonja, B, Luykx, JJ, Lyons, MJ, Maples-Keller, J, Marmar, C, Martin, AR, Martin, NG, Maurer, D, Mavissakalian, MR, McFarlane, A, McGlinchey, RE, McLaughlin, KA, McLean, SA, McLeay, S, Mehta, D, Milberg, WP, Miller, MW, Morey, RA, Morris, CP, Mors, O, Mortensen, PB, Neale, BM, Nelson, EC, Nordentoft, M, Norman, SB, O'Donnell, M, Orcutt, HK, Panizzon, MS, Peters, ES, Peterson, AL, Peverill, M, Pietrzak, RH, Polusny, MA, Rice, JP, Ripke, S, Risbrough, VB, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, K, Rung, A, Rutten, BPF, Saccone, NL, Sanchez, SE, Schijven, D, Seedat, S, Seligowski, A, Seng, JS, Sheerin, CM, Silove, D, Smith, AK, Smoller, JW, Sponheim, SR, Stein, DJ, Stevens, JS, Sumner, JA, Teicher, MH, Thompson, WK, Trapido, E, Uddin, M, Ursano, RJ, van den Heuvel, LL, Van Hooff, M, Vermetten, E, Vinkers, CH, Voisey, J, Wang, Y, Wang, Z, Werge, T, Williams, MA, Williamson, DE, Winternitz, S, Wolf, C, Wolf, EJ, Wolff, JD, Yehuda, R, Young, RM, Young, KA, Zhao, H, Zoellner, LA, Liberzon, I, Ressler, KJ, Haas, M & Koenen, KC 2019, 'International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci', Nature Communications, vol. 10, 4558. https://doi.org/10.1038/s41467-019-12576-w

TY - JOUR

T1 - International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

AU - Nievergelt, Caroline M.

AU - Maihofer, Adam X.

AU - Klengel, Torsten

AU - Atkinson, Elizabeth G.

AU - Chen, Chia-Yen

AU - Choi, Karmel W.

AU - Coleman, Jonathan R.

AU - Dalvie, Shareefa

AU - Duncan, Laramie E.

AU - Gelernter, Joel

AU - Levey, Daniel F.

AU - Logue, Mark W.

AU - Polimanti, Renato

AU - Provost, Allison C.

AU - Ratanatharathorn, Andrew

AU - Stein, Murray B.

AU - Torres, Katy

AU - Aiello, Allison E.

AU - Almli, Lynn M.

AU - Amstadter, Ananda B.

AU - Andersen, Sren B.

AU - Andreassen, Ole A.

AU - Arbisi, Paul A.

AU - Ashley-Koch, Allison E.

AU - Austin, S. Bryn

AU - Avdibegovic, Esmina

AU - Babic, Dragan

AU - Baekvad-Hansen, Marie

AU - Baker, Dewleen G.

AU - Beckham, Jean C.

AU - Bierut, Laura J.

AU - Bisson, Jonathan

AU - Boks, Marco P.

AU - Bolger, Elizabeth A.

AU - Brglum, Anders D.

AU - Bradley, Bekh

AU - Brashear, Megan

AU - Breen, Gerome

AU - Bryant, Richard A.

AU - Bustamante, Angela C.

AU - Bybjerg-Grauholm, Jonas

AU - Calabrese, Joseph R.

AU - Caldas-de-Almeida, Jose M.

AU - Dale, Anders M.

AU - Daly, Mark J.

AU - Daskalakis, Nikolaos P.

AU - Deckert, Juergen

AU - Delahanty, Douglas L.

AU - Dennis, Michelle F.

AU - Disner, Seth G.

AU - Domschke, Katharina

AU - Dzubur-Kulenovic, Alma

AU - Erbes, Christopher R.

AU - Evans, Alexandra

AU - Farrer, Lindsay A.

AU - Feeny, Norah C.

AU - Flory, Janine D.

AU - Forbes, David

AU - Franz, Carol E.

AU - Galea, Sandro

AU - Garrett, Melanie E.

AU - Gelaye, Bizu

AU - Geuze, Elbert

AU - Gillespie, Charles

AU - Uka, Aferdita Goci

AU - Gordon, Scott D.

AU - Guffanti, Guia

AU - Hammamieh, Rasha

AU - Harnal, Supriya

AU - Hauser, Michael A.

AU - Heath, Andrew C.

AU - Hemmings, Sian M. J.

AU - Hougaard, David Michael

AU - Jakovljevic, Miro

AU - Jett, Marti

AU - Johnson, Eric Otto

AU - Jones, Ian

AU - Jovanovic, Tanja

AU - Qin, Xue-Jun

AU - Junglen, Angela G.

AU - Karstoft, Karen-Inge

AU - Kaufman, Milissa L.

AU - Kessler, Ronald C.

AU - Khan, Alaptagin

AU - Kimbrel, Nathan A.

AU - King, Anthony P.

AU - Koen, Nastassja

AU - Kranzler, Henry R.

AU - Kremen, William S.

AU - Lawford, Bruce R.

AU - Lebois, Lauren A. M.

AU - Lewis, Catrin E.

AU - Linnstaedt, Sarah D.

AU - Lori, Adriana

AU - Lugonja, Bozo

AU - Luykx, Jurjen J.

AU - Lyons, Michael J.

AU - Maples-Keller, Jessica

AU - Marmar, Charles

AU - Martin, Alicia R.

AU - Martin, Nicholas G.

AU - Maurer, Douglas

AU - Mavissakalian, Matig R.

AU - McFarlane, Alexander

AU - McGlinchey, Regina E.

AU - McLaughlin, Katie A.

AU - McLean, Samuel A.

AU - McLeay, Sarah

AU - Mehta, Divya

AU - Milberg, William P.

AU - Miller, Mark W.

AU - Morey, Rajendra A.

AU - Morris, Charles Phillip

AU - Mors, Ole

AU - Mortensen, Preben B.

AU - Neale, Benjamin M.

AU - Nelson, Elliot C.

AU - Nordentoft, Merete

AU - Norman, Sonya B.

AU - O'Donnell, Meaghan

AU - Orcutt, Holly K.

AU - Panizzon, Matthew S.

AU - Peters, Edward S.

AU - Peterson, Alan L.

AU - Peverill, Matthew

AU - Pietrzak, Robert H.

AU - Polusny, Melissa A.

AU - Rice, John P.

AU - Ripke, Stephan

AU - Risbrough, Victoria B.

AU - Roberts, Andrea L.

AU - Rothbaum, Alex O.

AU - Rothbaum, Barbara O.

AU - Roy-Byrne, Peter

AU - Ruggiero, Ken

AU - Rung, Ariane

AU - Rutten, Bart P. F.

AU - Saccone, Nancy L.

AU - Sanchez, Sixto E.

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N1 - Funding Information: 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 (nonprofit) 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 Bio-pharmaceuticals, 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. Funding Information: This work was funded by Cohen Veterans Bioscience, the NIMH/U.S. Army Medical Research and Materiel Command Grant R01MH106595 to C.M.N., I.L., K.J.R. and K.C.K., One Mind, and supported by 5U01MH109539 to the Psychiatric Genomics Consortium. Statistical Analysis were carried out on the NL Genetic Cluster computer (URL) hosted by SURFsara. Genotyping of samples was supported in part through the Stanley Center for Psychiatric Genetics at the Broad Institute of MIT and Harvard. This research has been conducted using the UK biobank resource under application number 16577. This work would not have been possible without the contributions of the investigators who comprise the PGC-PTSD working group, and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. Full acknowledgements are in the Supplementary Note 2. Publisher Copyright: © 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

PY - 2019/10/8

Y1 - 2019/10/8

N2 - 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.

AB - 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.

KW - POSTTRAUMATIC-STRESS-DISORDER

KW - HUMAN DEMOGRAPHIC HISTORY

KW - LD SCORE REGRESSION

KW - PARKINSON DISEASE

KW - SNP HERITABILITY

KW - TRAUMA

KW - EFFICIENT

KW - PREVENTION

KW - PROFILES

KW - SYMPTOMS

U2 - 10.1038/s41467-019-12576-w

DO - 10.1038/s41467-019-12576-w

M3 - Article

C2 - 31594949

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 4558

ER -