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, Søren Bo Andersen, Ole A. Andreassen, Paul A. Arbisi, Allison E. Ashley‐Koch, S. Bryn Austin, Esmina Avdibegović, Anders D. Børglum, Dragan Babić, Marie Bækvad-Hansen, Dewleen G. Baker, Jean C. Beckham, Laura J. Bierut, Jonathan I. Bisson, Marco P. Boks, Elizabeth Bolger, Bekh Bradley, Meghan Brashear, Gerome Breen, Richard A. Bryant, Angela C. Bustamante, Jonas Bybjerg‐Grauholm, Joseph R. Calabrese, José Miguel 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, Afërdita Goçi, Scott D. Gordon, Guia Guffanti, Rasha Hammamieh, Michael A. Hauser, Andrew C. Heath, Sian Hemmings, David M. Hougaard, Miro Jakovljević, Marti Jett, Eric O. Johnson, Ian Jones, Tanja Jovanović, Xuejun 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 R. Marmar, Nicholas G. Martin, Douglas Maurer, Matig Mavissakalian
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.