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

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, Avdibegovic E, Borglum AD, Babic 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 Kulenovic 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, Jakovljevic 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 RM, 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. Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information. Biological psychiatry. 2022 Apr 1; 91(7):626-636.

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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.