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Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

By Caroline M. Nievergelt, Adam X. Maihofer, Torsten Klengel, Elizabeth G. Atkinson, Chia-Yen Chen, Karmel Choi, Jonathan R.I Coleman, Shareefa Dalvie, Laramie E Duncan, Mark W Logue, Allison C Provost, Andrew Ratanatharathorn, Murray B. Stein, Katy Torres, Allison E Aiello, Lynn M. Almli, Ananda B Amstadter, Søren B Andersen, Ole A Andreassen, Paul A Arbisi, Allison E Ashley-Koch, S Bryn Austin, Esmina Avdibegovic, Dragan Babić, Marie Bækvad-Hansen, Dewleen G Baker, Jean C Beckham, Laura J Bierut, Jonathan I Bisson, Marco P. Boks, Elizabeth A Bolger, Anders D. Borglum, Bekh Bradley, Megan Brashear, Gerome Breen, Richard A Bryant, Angela C Bustamante, Jonas Bybjerg-Grauholm, Joseph R Calabrese, José M. Caldas-de-Almeida, Anders M. Dale, Mark J. Daly, Nikolaos P. Daskalakis, Jürgen Deckert, Douglas L Delahanty, Michelle F Dennis, Seth G Disner, Katharina Domschke, Alma Dzubur-Kulenovic, Christopher R Erbes, Alexandra Evans, Lindsay A. Farrer, Norah C Feeny, Janine D Flory, David Forbes, Carol E. Franz, Sandro Galea, Melanie E. Garrett, Bizu Gelaye, Joel Gelernter, Elbert Geuze, Charles Gillespie, Aferdita Goci Uka, Scott D Gordon, Guia Guffanti, Rasha Hammamieh, Supriya Harnal, Michael A. Hauser, Andrew C. Heath, Sian M.J. Hemmings, David Michael Hougaard, Miro Jakovljevic, Marti Jett, Eric Otto Johnson, Ian Jones, Tanja Jovanovic, Xue-Jun Qin, Angela G Junglen, 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 E Lewis, Sarah D Linnstaedt, Adriana Lori, Bozo Lugonja, Jurjen J. Luykx, Michael J. Lyons, Jessica Maples-Keller, Charles Marmar, Alicia R. Martin, Nicholas G Martin, Douglas Maurer, Matig R Mavissakalian, Alexander McFarlane, Regina E McGlinchey, Katie A. McLaughlin, Samuel A McLean, Sarah McLeay, Divya Mehta, William P Milberg, Mark W Miller, Rajendra A. Morey, Charles Phillip Morris, Ole Mors, Preben B Mortensen, Benjamin M Neale, 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, Stephan Ripke, Victoria B Risbrough, Andrea L Roberts, Alex O Rothbaum, Barbara O Rothbaum, Peter Roy-Byrne, Ken 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, Nadia Solovieff, Scott R. Sponheim, Dan J. Stein, Jennifer A Sumner, 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, Jonathan D Wolff, Rachel Yehuda, Keith A. Young, Ross McD. Young, Hongyu Zhao, Lori A Zoellner, Israel Liberzon, Kerry J. Ressler, Magali Haas, Karestan C. Koenen

Posted 01 Nov 2018
bioRxiv DOI: 10.1101/458562

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson's Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

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