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 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, 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 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

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.

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
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
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
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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