Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Adam X. Maihofer; Karmel W. Choi; Jonathan R.I. Coleman; Nikolaos P. Daskalakis; Christy A. Denckla; Elizabeth Ketema; Rajendra A. Morey; Renato Polimanti; Andrew Ratanatharathorn; Katy Torres; Aliza P. Wingo; Clement C. Zai; Allison E. Aiello; Lynn M. Almli; Ananda B. Amstadter; Soren B. Andersen; Ole A. Andreassen; Paul A. Arbisi; Allison E. Ashley-Koch; S. Bryn Austin; Esmina Avdibegović; Anders D. Borglum; Dragan Babić; Marie Bækvad-Hansen; Dewleen G. Baker; Jean C. Beckham; Laura J. Bierut; Jonathan I. Bisson; Marco P. Boks; Elizabeth A. Bolger; Bekh Bradley; Meghan Brashear; Gerome Breen; Richard A. Bryant; Angela C. Bustamante; Jonas Bybjerg-Grauholm; Joseph R. Calabrese; José M. Caldas-de-Almeida; Chia Yen Chen; Anders M. Dale; Shareefa Dalvie; Jürgen Deckert; Douglas L. Delahanty; Michelle F. Dennis; Seth G. Disner; Katharina Domschke; Laramie E. Duncan; Alma Džubur Kulenović; Christopher R. Erbes; Alexandra Evans; Lindsay A. Farrer; Norah C. Feeny; Janine D. Flory; David Forbes; Carol E. Franz; Sandro Galea; Melanie E. Garrett; Aarti Gautam; Bizu Gelaye; Joel Gelernter; Elbert Geuze; Charles F. Gillespie; Aferdita Goçi; Scott D. Gordon; Guia Guffanti; Rasha Hammamieh; Michael A. Hauser; Andrew C. Heath; Sian M.J. Hemmings; David Michael Hougaard; Miro Jakovljević; Marti Jett; Eric Otto Johnson; Ian Jones; Tanja Jovanovic; Xue Jun Qin; 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 Lewis; Israel Liberzon; Sarah D. Linnstaedt; Mark W. Logue; Adriana Lori; Božo Lugonja; Jurjen J. Luykx; Michael J. Lyons; Jessica L. Maples-Keller; Charles Marmar; Nicholas G. Martin; Douglas Maurer; Matig R. Mavissakalian; Alexander McFarlane; Regina E. McGlinchey; Katie A. McLaughlin; Samuel A. McLean; Divya Mehta; Rebecca Mellor; Vasiliki Michopoulos; William Milberg; Mark W. Miller; Charles Phillip Morris; Ole Mors; Preben B. Mortensen; 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; Victoria B. Risbrough; Andrea L. Roberts; Alex O. Rothbaum; Barbara O. Rothbaum; Peter Roy-Byrne; Kenneth J. 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; 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; Rachel Yehuda; Keith A. Young; Ross Mc D. Young; Hongyu Zhao; Lori A. Zoellner; Magali Haas; Heather Lasseter; Allison C. Provost; Rany M. Salem; Jonathan Sebat; Richard A. Shaffer; Tianying Wu; Stephan Ripke; Mark J. Daly; Kerry J. Ressler; Karestan C. Koenen; Murray B. Stein; Caroline M. Nievergelt

doi:10.1016/j.biopsych.2021.09.020

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Adam X. Maihofer, Karmel W. Choi, Jonathan R.I. Coleman, Nikolaos P. Daskalakis, Christy A. Denckla, Elizabeth Ketema, Rajendra A. Morey, Renato Polimanti, Andrew Ratanatharathorn, Katy Torres, Aliza P. Wingo, Clement C. Zai, Allison E. Aiello, Lynn M. Almli, Ananda B. Amstadter, Soren B. Andersen, Ole A. Andreassen, Paul A. Arbisi, Allison E. Ashley-Koch, S. Bryn AustinEsmina Avdibegović, Anders D. Borglum, Dragan Babić, Marie Bækvad-Hansen, Dewleen G. Baker, Jean C. Beckham, Laura J. Bierut, Jonathan I. Bisson, Marco P. Boks, Elizabeth A. Bolger, Bekh Bradley, Meghan Brashear, Gerome Breen, Richard A. Bryant, Angela C. Bustamante, Jonas Bybjerg-Grauholm, Joseph R. Calabrese, José M. Caldas-de-Almeida, Chia Yen Chen, Anders M. Dale, Shareefa Dalvie, Jürgen Deckert, Douglas L. Delahanty, Michelle F. Dennis, Seth G. Disner, Katharina Domschke, Laramie E. Duncan, Alma Džubur Kulenović, Christopher R. Erbes, Alexandra Evans, Lindsay A. Farrer, Norah C. Feeny, Janine D. Flory, David Forbes, Carol E. Franz, Sandro Galea, Melanie E. Garrett, Aarti Gautam, Bizu Gelaye, Joel Gelernter, Elbert Geuze, Charles F. Gillespie, Aferdita Goçi, Scott D. Gordon, Guia Guffanti, Rasha Hammamieh, Michael A. Hauser, Andrew C. Heath, Sian M.J. Hemmings, David Michael Hougaard, Miro Jakovljević, Marti Jett, Eric Otto Johnson, Ian Jones, Tanja Jovanovic, Xue Jun Qin, 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 Lewis, Israel Liberzon, Sarah D. Linnstaedt, Mark W. Logue, Adriana Lori, Božo Lugonja, Jurjen J. Luykx, Michael J. Lyons, Jessica L. Maples-Keller, Charles Marmar, Nicholas G. Martin, Douglas Maurer, Matig R. Mavissakalian, Alexander McFarlane, Regina E. McGlinchey, Katie A. McLaughlin, Samuel A. McLean, Divya Mehta, Rebecca Mellor, Vasiliki Michopoulos, William Milberg, Mark W. Miller, Charles Phillip Morris, Ole Mors, Preben B. Mortensen, 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, Victoria B. Risbrough, Andrea L. Roberts, Alex O. Rothbaum, Barbara O. Rothbaum, Peter Roy-Byrne, Kenneth J. 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, 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, Rachel Yehuda, Keith A. Young, Ross Mc D. Young, Hongyu Zhao, Lori A. Zoellner, Magali Haas, Heather Lasseter, Allison C. Provost, Rany M. Salem, Jonathan Sebat, Richard A. Shaffer, Tianying Wu, Stephan Ripke, Mark J. Daly, Kerry J. Ressler, Karestan C. Koenen, Murray B. Stein, Caroline M. Nievergelt

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

12 Scopus citations

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	https://doi.org/10.1016/j.biopsych.2021.09.020
State	Published - Apr 1 2022

Keywords

GWAS
Genetics
Heritability
PTSD
PheWAS
Trauma

Access to Document

10.1016/j.biopsych.2021.09.020

Cite this

Maihofer, A. X., Choi, K. W., Coleman, J. R. I., Daskalakis, N. P., Denckla, C. A., Ketema, E., Morey, R. A., Polimanti, R., Ratanatharathorn, A., Torres, K., Wingo, A. P., Zai, C. C., Aiello, A. E., Almli, L. M., Amstadter, A. B., Andersen, S. B., Andreassen, O. A., Arbisi, P. A., Ashley-Koch, A. E., ... Nievergelt, C. M. (2022). Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information. Biological Psychiatry, 91(7), 626-636. https://doi.org/10.1016/j.biopsych.2021.09.020

@article{dce277e5e496438da36d982c458493fc,

title = "Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information",

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.",

keywords = "GWAS, Genetics, Heritability, PTSD, PheWAS, Trauma",

author = "Maihofer, {Adam X.} and Choi, {Karmel W.} and Coleman, {Jonathan R.I.} and Daskalakis, {Nikolaos P.} and Denckla, {Christy A.} and Elizabeth Ketema and Morey, {Rajendra A.} and Renato Polimanti and Andrew Ratanatharathorn and Katy Torres and Wingo, {Aliza P.} and Zai, {Clement C.} and Aiello, {Allison E.} and Almli, {Lynn M.} and Amstadter, {Ananda B.} and Andersen, {Soren B.} and Andreassen, {Ole A.} and Arbisi, {Paul A.} and Ashley-Koch, {Allison E.} and Austin, {S. Bryn} and Esmina Avdibegovi{\'c} and Borglum, {Anders D.} and Dragan Babi{\'c} and Marie B{\ae}kvad-Hansen and Baker, {Dewleen G.} and Beckham, {Jean C.} and Bierut, {Laura J.} and Bisson, {Jonathan I.} and Boks, {Marco P.} and Bolger, {Elizabeth A.} and Bekh Bradley and Meghan Brashear and Gerome Breen and Bryant, {Richard A.} and Bustamante, {Angela C.} and Jonas Bybjerg-Grauholm and Calabrese, {Joseph R.} and Caldas-de-Almeida, {Jos{\'e} M.} and Chen, {Chia Yen} and Dale, {Anders M.} and Shareefa Dalvie and J{\"u}rgen Deckert and Delahanty, {Douglas L.} and Dennis, {Michelle F.} and Disner, {Seth G.} and Katharina Domschke and Duncan, {Laramie E.} and {D{\v z}ubur Kulenovi{\'c}}, Alma 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 Aarti Gautam and Bizu Gelaye and Joel Gelernter and Elbert Geuze and Gillespie, {Charles F.} and Aferdita Go{\c c}i and Gordon, {Scott D.} and Guia Guffanti and Rasha Hammamieh and Hauser, {Michael A.} and Heath, {Andrew C.} and Hemmings, {Sian M.J.} and Hougaard, {David Michael} and Miro Jakovljevi{\'c} and Marti Jett and Johnson, {Eric Otto} and Ian Jones and Tanja Jovanovic and Qin, {Xue Jun} and Karstoft, {Karen Inge} 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 Catrin Lewis and Israel Liberzon and Linnstaedt, {Sarah D.} and Logue, {Mark W.} and Adriana Lori and Bo{\v z}o Lugonja and Luykx, {Jurjen J.} and Lyons, {Michael J.} and Maples-Keller, {Jessica L.} and Charles Marmar 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 Divya Mehta and Rebecca Mellor and Vasiliki Michopoulos and William Milberg and Miller, {Mark W.} and Morris, {Charles Phillip} and Ole Mors and Mortensen, {Preben B.} 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 Risbrough, {Victoria B.} and Roberts, {Andrea L.} and Rothbaum, {Alex O.} and Rothbaum, {Barbara O.} and Peter Roy-Byrne and Ruggiero, {Kenneth J.} and Ariane Rung and Rutten, {Bart P.F.} and Saccone, {Nancy L.} and Sanchez, {Sixto E.} and Dick Schijven and Soraya Seedat and Seligowski, {Antonia V.} 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 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 Rachel Yehuda and Young, {Keith A.} and Young, {Ross Mc D.} and Hongyu Zhao and Zoellner, {Lori A.} and Magali Haas and Heather Lasseter and Provost, {Allison C.} and Salem, {Rany M.} and Jonathan Sebat and Shaffer, {Richard A.} and Tianying Wu and Stephan Ripke and Daly, {Mark J.} and Ressler, {Kerry J.} and Koenen, {Karestan C.} and Stein, {Murray B.} and Nievergelt, {Caroline M.}",

note = "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: {\textcopyright} 2021 Society of Biological Psychiatry",

year = "2022",

month = apr,

day = "1",

doi = "10.1016/j.biopsych.2021.09.020",

language = "English",

volume = "91",

pages = "626--636",

journal = "Biological Psychiatry",

issn = "0006-3223",

number = "7",

}

Maihofer, AX, Choi, KW, Coleman, JRI, Daskalakis, NP, Denckla, CA, Ketema, E, Morey, RA, Polimanti, R, Ratanatharathorn, A, Torres, K, Wingo, AP, Zai, CC, Aiello, AE, Almli, LM, Amstadter, AB, Andersen, SB, Andreassen, OA, Arbisi, PA, Ashley-Koch, AE, Austin, SB, Avdibegović, E, Borglum, AD, Babić, D, Bækvad-Hansen, M, Baker, DG, Beckham, JC, Bierut, LJ, Bisson, JI, Boks, MP, Bolger, EA, Bradley, B, Brashear, M, Breen, G, Bryant, RA, Bustamante, AC, Bybjerg-Grauholm, J, Calabrese, JR, Caldas-de-Almeida, JM, Chen, CY, Dale, AM, Dalvie, S, Deckert, J, Delahanty, DL, Dennis, MF, Disner, SG, Domschke, K, Duncan, LE, Džubur Kulenović, A, Erbes, CR, Evans, A, Farrer, LA, Feeny, NC, Flory, JD, Forbes, D, Franz, CE, Galea, S, Garrett, ME, Gautam, A, Gelaye, B, Gelernter, J, Geuze, E, Gillespie, CF, Goçi, A, Gordon, SD, Guffanti, G, Hammamieh, R, Hauser, MA, Heath, AC, Hemmings, SMJ, Hougaard, DM, Jakovljević, M, Jett, M, Johnson, EO, Jones, I, Jovanovic, T, Qin, XJ, Karstoft, KI, Kaufman, ML, Kessler, RC, Khan, A, Kimbrel, NA, King, AP, Koen, N, Kranzler, HR, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, C, Liberzon, I, Linnstaedt, SD, Logue, MW, Lori, A, Lugonja, B, Luykx, JJ, Lyons, MJ, Maples-Keller, JL, Marmar, C, Martin, NG, Maurer, D, Mavissakalian, MR, McFarlane, A, McGlinchey, RE, McLaughlin, KA, McLean, SA, Mehta, D, Mellor, R, Michopoulos, V, Milberg, W, Miller, MW, Morris, CP, Mors, O, Mortensen, PB, 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, Risbrough, VB, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, KJ, Rung, A, Rutten, BPF, Saccone, NL, Sanchez, SE, Schijven, D, Seedat, S, Seligowski, AV, Seng, JS, Sheerin, CM, Silove, D, Smith, AK, Smoller, JW, Sponheim, SR, Stein, DJ, Stevens, JS, 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, Yehuda, R, Young, KA, Young, RMD, Zhao, H, Zoellner, LA, Haas, M, Lasseter, H, Provost, AC, Salem, RM, Sebat, J, Shaffer, RA, Wu, T, Ripke, S, Daly, MJ, Ressler, KJ, Koenen, KC, Stein, MB & Nievergelt, CM 2022, 'Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information', Biological Psychiatry, vol. 91, no. 7, pp. 626-636. https://doi.org/10.1016/j.biopsych.2021.09.020

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.

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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 -

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

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