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

2022-04-01Artigo científico Acesso aberto
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dc.contributor.authorMaihofer, Adam X.
dc.contributor.authorChoi, Karmel W.
dc.contributor.authorColeman, Jonathan R.I.
dc.contributor.authorDaskalakis, Nikolaos P.
dc.contributor.authorDenckla, Christy A.
dc.contributor.authorKetema, Elizabeth
dc.contributor.authorMorey, Rajendra A.
dc.contributor.authorPolimanti, Renato
dc.contributor.authorRatanatharathorn, Andrew
dc.contributor.authorTorres, Katy
dc.contributor.authorWingo, Aliza P.
dc.contributor.authorZai, Clement C.
dc.contributor.authorAiello, Allison E.
dc.contributor.authorAlmli, Lynn M.
dc.contributor.authorAmstadter, Ananda B.
dc.contributor.authorAndersen, Soren B.
dc.contributor.authorAndreassen, Ole A.
dc.contributor.authorArbisi, Paul A.
dc.contributor.authorAshley-Koch, Allison E.
dc.contributor.authorAustin, S. Bryn
dc.contributor.authorAvdibegović, Esmina
dc.contributor.authorBorglum, Anders D.
dc.contributor.authorBabić, Dragan
dc.contributor.authorBækvad-Hansen, Marie
dc.contributor.authorBaker, Dewleen G.
dc.contributor.authorBeckham, Jean C.
dc.contributor.authorBierut, Laura J.
dc.contributor.authorBisson, Jonathan I.
dc.contributor.authorBoks, Marco P.
dc.contributor.authorBolger, Elizabeth A.
dc.contributor.authorBradley, Bekh
dc.contributor.authorJM, Caldas-de-Almeida
dc.contributor.authorBrashear, Meghan
dc.contributor.authorBreen, Gerome
dc.contributor.authorBryant, Richard A.
dc.contributor.authorBustamante, Angela C.
dc.contributor.authorBybjerg-Grauholm, Jonas
dc.contributor.authorCalabrese, Joseph R.
dc.contributor.authorCaldas-de-Almeida, José M.
dc.contributor.authorChen, Chia Yen
dc.contributor.authorDale, Anders M.
dc.contributor.authorDalvie, Shareefa
dc.contributor.authorDeckert, Jürgen
dc.contributor.authorDelahanty, Douglas L.
dc.contributor.authorDennis, Michelle F.
dc.contributor.authorDisner, Seth G.
dc.contributor.authorDomschke, Katharina
dc.contributor.authorDuncan, Laramie E.
dc.contributor.authorDžubur Kulenović, Alma
dc.contributor.authorErbes, Christopher R.
dc.contributor.authorEvans, Alexandra
dc.contributor.authorFarrer, Lindsay A.
dc.contributor.authorFeeny, Norah C.
dc.contributor.authorFlory, Janine D.
dc.contributor.authorForbes, David
dc.contributor.authorFranz, Carol E.
dc.contributor.authorGalea, Sandro
dc.contributor.authorGarrett, Melanie E.
dc.contributor.authorGautam, Aarti
dc.contributor.authorGelaye, Bizu
dc.contributor.authorGelernter, Joel
dc.contributor.authorGeuze, Elbert
dc.contributor.authorGillespie, Charles F.
dc.contributor.authorGoçi, Aferdita
dc.contributor.authorGordon, Scott D.
dc.contributor.authorGuffanti, Guia
dc.contributor.authorHammamieh, Rasha
dc.contributor.authorHauser, Michael A.
dc.contributor.authorHeath, Andrew C.
dc.contributor.authorHemmings, Sian M.J.
dc.contributor.authorHougaard, David Michael
dc.contributor.authorJakovljević, Miro
dc.contributor.authorJett, Marti
dc.contributor.authorJohnson, Eric Otto
dc.contributor.authorJones, Ian
dc.contributor.authorJovanovic, Tanja
dc.contributor.authorQin, Xue Jun
dc.contributor.authorKessler, Ronald
dc.contributor.authorKarstoft, Karen Inge
dc.contributor.authorKaufman, Milissa L.
dc.contributor.authorKessler, Ronald C.
dc.contributor.authorKhan, Alaptagin
dc.contributor.authorKimbrel, Nathan A.
dc.contributor.authorKing, Anthony P.
dc.contributor.authorKoen, Nastassja
dc.contributor.authorKranzler, Henry R.
dc.contributor.authorKremen, William S.
dc.contributor.authorLawford, Bruce R.
dc.contributor.authorLebois, Lauren A.M.
dc.contributor.authorLewis, Catrin
dc.contributor.authorLiberzon, Israel
dc.contributor.authorLinnstaedt, Sarah D.
dc.contributor.authorLogue, Mark W.
dc.contributor.authorLori, Adriana
dc.contributor.authorLugonja, Božo
dc.contributor.authorLuykx, Jurjen J.
dc.contributor.authorLyons, Michael J.
dc.contributor.authorMaples-Keller, Jessica L.
dc.contributor.authorMarmar, Charles
dc.contributor.authorMartin, Nicholas G.
dc.contributor.authorMaurer, Douglas
dc.contributor.authorMavissakalian, Matig R.
dc.contributor.authorMcFarlane, Alexander
dc.contributor.authorMcGlinchey, Regina E.
dc.contributor.authorMcLaughlin, Katie A.
dc.contributor.authorMcLean, Samuel A.
dc.contributor.authorMehta, Divya
dc.contributor.authorMellor, Rebecca
dc.contributor.authorMichopoulos, Vasiliki
dc.contributor.authorMilberg, William
dc.contributor.authorMiller, Mark W.
dc.contributor.authorMorris, Charles Phillip
dc.contributor.authorMors, Ole
dc.contributor.authorMortensen, Preben B.
dc.contributor.authorNelson, Elliot C.
dc.contributor.authorNordentoft, Merete
dc.contributor.authorNorman, Sonya B.
dc.contributor.authorO'Donnell, Meaghan
dc.contributor.authorOrcutt, Holly K.
dc.contributor.authorPanizzon, Matthew S.
dc.contributor.authorPeters, Edward S.
dc.contributor.authorPeterson, Alan L.
dc.contributor.authorPeverill, Matthew
dc.contributor.authorPietrzak, Robert H.
dc.contributor.authorPolusny, Melissa A.
dc.contributor.authorRice, John P.
dc.contributor.authorRisbrough, Victoria B.
dc.contributor.authorRoberts, Andrea L.
dc.contributor.authorRothbaum, Alex O.
dc.contributor.authorRothbaum, Barbara O.
dc.contributor.authorRoy-Byrne, Peter
dc.contributor.authorRuggiero, Kenneth J.
dc.contributor.authorRung, Ariane
dc.contributor.authorRutten, Bart P.F.
dc.contributor.authorSaccone, Nancy L.
dc.contributor.authorSanchez, Sixto E.
dc.contributor.authorSchijven, Dick
dc.contributor.authorSeedat, Soraya
dc.contributor.authorSeligowski, Antonia V.
dc.contributor.authorSeng, Julia S.
dc.contributor.authorSheerin, Christina M.
dc.contributor.authorSilove, Derrick
dc.contributor.authorSmith, Alicia K.
dc.contributor.authorSmoller, Jordan W.
dc.contributor.authorSponheim, Scott R.
dc.contributor.authorStein, Dan J.
dc.contributor.authorStevens, Jennifer S.
dc.contributor.authorTeicher, Martin H.
dc.contributor.authorThompson, Wesley K.
dc.contributor.authorTrapido, Edward
dc.contributor.authorUddin, Monica
dc.contributor.authorUrsano, Robert J.
dc.contributor.authorvan den Heuvel, Leigh Luella
dc.contributor.authorVan Hooff, Miranda
dc.contributor.authorVermetten, Eric
dc.contributor.authorVinkers, Christiaan
dc.contributor.authorVoisey, Joanne
dc.contributor.authorWang, Yunpeng
dc.contributor.authorWang, Zhewu
dc.contributor.authorWerge, Thomas
dc.contributor.authorWilliams, Michelle A.
dc.contributor.authorWilliamson, Douglas E.
dc.contributor.authorWinternitz, Sherry
dc.contributor.authorWolf, Christiane
dc.contributor.authorWolf, Erika J.
dc.contributor.authorYehuda, Rachel
dc.contributor.authorYoung, Keith A.
dc.contributor.authorYoung, Ross Mc D.
dc.contributor.authorZhao, Hongyu
dc.contributor.authorZoellner, Lori A.
dc.contributor.authorHaas, Magali
dc.contributor.authorLasseter, Heather
dc.contributor.authorProvost, Allison C.
dc.contributor.authorSalem, Rany M.
dc.contributor.authorSebat, Jonathan
dc.contributor.authorShaffer, Richard A.
dc.contributor.authorWu, Tianying
dc.contributor.authorRipke, Stephan
dc.contributor.authorDaly, Mark J.
dc.contributor.authorRessler, Kerry J.
dc.contributor.authorKoenen, Karestan C.
dc.contributor.authorStein, Murray B.
dc.contributor.authorNievergelt, Caroline M.
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.pblElsevier Science B.V., Amsterdam.
dc.date.accessioned2021-12-22T23:25:56Z
dc.date.available2021-12-22T23:25:56Z
dc.date.issued2022-04-01
dc.descriptionFunding 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
dc.description.abstractBackground: 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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent953702
dc.identifier.doi10.1016/j.biopsych.2021.09.020
dc.identifier.issn0006-3223
dc.identifier.otherPURE: 35418233
dc.identifier.otherPURE UUID: 54fd7e20-5a4c-43f0-a91c-0f2fd4b4e8e8
dc.identifier.otherScopus: 85120747015
dc.identifier.otherPubMed: 34865855
dc.identifier.otherWOS: 000819789200005
dc.identifier.urihttp://hdl.handle.net/10362/129670
dc.identifier.urlhttps://www.scopus.com/pages/publications/85120747015
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGenetics
dc.subjectGWAS
dc.subjectHeritability
dc.subjectPheWAS
dc.subjectPTSD
dc.subjectTrauma
dc.subjectBiological Psychiatry
dc.titleEnhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Informationen
dc.typejournal article
degois.publication.firstPage626
degois.publication.issue7
degois.publication.lastPage636
degois.publication.titleBiological Psychiatry
degois.publication.volume91
dspace.entity.typePublication
person.familyNamecaldas de almeida
person.familyNameKessler
person.givenNamejosé miguel
person.givenNameRonald
person.identifier.ciencia-idA217-C270-9BA2
person.identifier.orcid0000-0003-1902-6772
person.identifier.orcid0000-0003-4831-2305
person.identifier.scopus-author-id6506787166
rcaap.rightsopenAccess
relation.isAuthorOfPublicationb48afbbc-5703-4b0f-8c88-6beb5432d327
relation.isAuthorOfPublication6c1a1bfc-ebea-4ec9-9e0b-ee83533fa86f
relation.isAuthorOfPublication.latestForDiscovery6c1a1bfc-ebea-4ec9-9e0b-ee83533fa86f

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