Abstract
Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.
Original language | English |
---|---|
Pages (from-to) | 626-636 |
Number of pages | 11 |
Journal | Biological Psychiatry |
Volume | 91 |
Issue number | 7 |
DOIs | |
State | Published - Apr 1 2022 |
Keywords
- GWAS
- Genetics
- Heritability
- PTSD
- PheWAS
- Trauma
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In: Biological Psychiatry, Vol. 91, No. 7, 01.04.2022, p. 626-636.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information
AU - Maihofer, Adam X.
AU - Choi, Karmel W.
AU - Coleman, Jonathan R.I.
AU - Daskalakis, Nikolaos P.
AU - Denckla, Christy A.
AU - Ketema, Elizabeth
AU - Morey, Rajendra A.
AU - Polimanti, Renato
AU - Ratanatharathorn, Andrew
AU - Torres, Katy
AU - Wingo, Aliza P.
AU - Zai, Clement C.
AU - Aiello, Allison E.
AU - Almli, Lynn M.
AU - Amstadter, Ananda B.
AU - Andersen, Soren B.
AU - Andreassen, Ole A.
AU - Arbisi, Paul A.
AU - Ashley-Koch, Allison E.
AU - Austin, S. Bryn
AU - Avdibegović, Esmina
AU - Borglum, Anders D.
AU - Babić, Dragan
AU - Bækvad-Hansen, Marie
AU - Baker, Dewleen G.
AU - Beckham, Jean C.
AU - Bierut, Laura J.
AU - Bisson, Jonathan I.
AU - Boks, Marco P.
AU - Bolger, Elizabeth A.
AU - Bradley, Bekh
AU - Brashear, Meghan
AU - Breen, Gerome
AU - Bryant, Richard A.
AU - Bustamante, Angela C.
AU - Bybjerg-Grauholm, Jonas
AU - Calabrese, Joseph R.
AU - Caldas-de-Almeida, José M.
AU - Chen, Chia Yen
AU - Dale, Anders M.
AU - Dalvie, Shareefa
AU - Deckert, Jürgen
AU - Delahanty, Douglas L.
AU - Dennis, Michelle F.
AU - Disner, Seth G.
AU - Domschke, Katharina
AU - Duncan, Laramie E.
AU - Džubur Kulenović, 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 - Gautam, Aarti
AU - Gelaye, Bizu
AU - Gelernter, Joel
AU - Geuze, Elbert
AU - Gillespie, Charles F.
AU - Goçi, Aferdita
AU - Gordon, Scott D.
AU - Guffanti, Guia
AU - Hammamieh, Rasha
AU - Hauser, Michael A.
AU - Heath, Andrew C.
AU - Hemmings, Sian M.J.
AU - Hougaard, David Michael
AU - Jakovljević, Miro
AU - Jett, Marti
AU - Johnson, Eric Otto
AU - Jones, Ian
AU - Jovanovic, Tanja
AU - Qin, Xue Jun
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
AU - Liberzon, Israel
AU - Linnstaedt, Sarah D.
AU - Logue, Mark W.
AU - Lori, Adriana
AU - Lugonja, Božo
AU - Luykx, Jurjen J.
AU - Lyons, Michael J.
AU - Maples-Keller, Jessica L.
AU - Marmar, Charles
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 - Mehta, Divya
AU - Mellor, Rebecca
AU - Michopoulos, Vasiliki
AU - Milberg, William
AU - Miller, Mark W.
AU - Morris, Charles Phillip
AU - Mors, Ole
AU - Mortensen, Preben B.
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 - Risbrough, Victoria B.
AU - Roberts, Andrea L.
AU - Rothbaum, Alex O.
AU - Rothbaum, Barbara O.
AU - Roy-Byrne, Peter
AU - Ruggiero, Kenneth J.
AU - Rung, Ariane
AU - Rutten, Bart P.F.
AU - Saccone, Nancy L.
AU - Sanchez, Sixto E.
AU - Schijven, Dick
AU - Seedat, Soraya
AU - Seligowski, Antonia V.
AU - Seng, Julia S.
AU - Sheerin, Christina M.
AU - Silove, Derrick
AU - Smith, Alicia K.
AU - Smoller, Jordan W.
AU - Sponheim, Scott R.
AU - Stein, Dan J.
AU - Stevens, Jennifer S.
AU - Teicher, Martin H.
AU - Thompson, Wesley K.
AU - Trapido, Edward
AU - Uddin, Monica
AU - Ursano, Robert J.
AU - van den Heuvel, Leigh Luella
AU - Van Hooff, Miranda
AU - Vermetten, Eric
AU - Vinkers, Christiaan H.
AU - Voisey, Joanne
AU - Wang, Yunpeng
AU - Wang, Zhewu
AU - Werge, Thomas
AU - Williams, Michelle A.
AU - Williamson, Douglas E.
AU - Winternitz, Sherry
AU - Wolf, Christiane
AU - Wolf, Erika J.
AU - Yehuda, Rachel
AU - Young, Keith A.
AU - Young, Ross Mc D.
AU - Zhao, Hongyu
AU - Zoellner, Lori A.
AU - Haas, Magali
AU - Lasseter, Heather
AU - Provost, Allison C.
AU - Salem, Rany M.
AU - Sebat, Jonathan
AU - Shaffer, Richard A.
AU - Wu, Tianying
AU - Ripke, Stephan
AU - Daly, Mark J.
AU - Ressler, Kerry J.
AU - Koenen, Karestan C.
AU - Stein, Murray B.
AU - Nievergelt, Caroline M.
N1 - Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank 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. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.
AB - Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.
KW - GWAS
KW - Genetics
KW - Heritability
KW - PTSD
KW - PheWAS
KW - Trauma
UR - http://www.scopus.com/inward/record.url?scp=85120747015&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2021.09.020
DO - 10.1016/j.biopsych.2021.09.020
M3 - Article
C2 - 34865855
AN - SCOPUS:85120747015
SN - 0006-3223
VL - 91
SP - 626
EP - 636
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 7
ER -