Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders
Authors: Nievergelt Caroline M , Maihofer Adam X , Atkinson Elizabeth G , Chen Chia-Yen , Choi Karmel W , Coleman Jonathan RI , Daskalakis Nikolaos P , Duncan Laramie E , Polimanti Renato , Aaronson Cindy , Amstadter Ananda B , Andersen Soren B , Andreassen Ole A , Arbisi Paul A , Ashley-Koch Allison E , Austin S Bryn , Avdibegoviç Esmina , Babic Dragan , Bacanu Silviu-Alin , Baker Dewleen G , Batzler Anthony , Beckham Jean C , Belangero Sintia , Benjet Corina , Bergner Carisa , Bierer Linda M , Biernacka Joanna M , Bierut Laura J , Bisson Jonathan I , Boks Marco P , Bolger Elizabeth A , Brandolino Amber , Breen Gerome , Bressan Rodrigo Affonseca , Bryant Richard A , Bustamante Angela C , Bybjerg-Grauholm Jonas , Bækvad-Hansen Marie , Børglum Anders D , Børte Sigrid , Cahn Leah , Calabrese Joseph R , Caldas-de-Almeida Jose Miguel , Chatzinakos Chris , Cheema Sheraz , Clouston Sean A P , Colodro-Conde LucÍa , Coombes Brandon J , Cruz-Fuentes Carlos S , Dale Anders M , Dalvie Shareefa , Davis Lea K , Deckert Jürgen , Delahanty Douglas L , Dennis Michelle F , deRoon-Cassini Terri , Desarnaud Frank , DiPietro Christopher P , Disner Seth G , Docherty Anna R , Domschke Katharina , Dyb Grete , Kulenovic Alma Dzubur , Edenberg Howard J , Evans Alexandra , Fabbri Chiara , Fani Negar , Farrer Lindsay A , Feder Adriana , Feeny Norah C , Flory Janine D , Forbes David , Franz Carol E , Galea Sandro , Garrett Melanie E , Gelaye Bizu , Gelernter Joel , Geuze Elbert , Gillespie Charles F , Goci Aferdita , Goleva Slavina B , Gordon Scott D , Grasser Lana Ruvolo , Guindalini Camila , Haas Magali , Hagenaars Saskia , Hauser Michael A , Heath Andrew C , Hemmings Sian MJ , Hesselbrock Victor , Hickie Ian B , Hogan Kelleigh , Hougaard David Michael , Huang Hailiang , Huckins Laura M , Hveem Kristian , Jakovljevic Miro , Javanbakht Arash , Jenkins Gregory D , Johnson Jessica , Jones Ian , Jovanovic Tanja , Karstoft Karen-Inge , Kaufman Milissa L , Kennedy James L , Kessler Ronald C , Khan Alaptagin , Kimbrel Nathan A , King Anthony P , Koen Nastassja , Kotov Roman , Kranzler Henry R , Krebs Kristi , Kremen William S , Kuan Pei-Fen , Lawford Bruce R , Lebois Lauren A M , Lehto Kelli , Levey Daniel F , Lewis Catrin , Liberzon Israel , Linnstaedt Sarah D , Logue Mark W , Lori Adriana , Lu Yi , Luft Benjamin J , Lupton Michelle K , Luykx Jurjen J , Makotkine Iouri , Maples-Keller Jessica L , Marchese Shelby , Marmar Charles , Martin Nicholas G , MartÍnez-Levy Gabriela A , McAloney Kerrie , McFarlane Alexander , McLaughlin Katie A , McLean Samuel A , Medland Sarah E , Mehta Divya , Meyers Jacquelyn , Michopoulos Vasiliki , Mikita Elizabeth A , Milani Lili , Milberg William , Miller Mark W , Morey Rajendra A , Morris Charles Phillip , Mors Ole , Mortensen Preben Bo , Mufford Mary S , Nelson Elliot C , Nordentoft Merete , Norman Sonya B , Nugent Nicole R , O’Donnell Meaghan , Orcutt Holly K , Pan Pedro M , Panizzon Matthew S , Pathak Gita A , Peters Edward S , Peterson Alan L , Peverill Matthew , Pietrzak Robert H , Polusny Melissa A , Porjesz Bernice , Powers Abigail , Qin Xue-Jun , Ratanatharathorn Andrew , Risbrough Victoria B , Roberts Andrea L , Rothbaum Barbara O , Rothbaum Alex O , Roy-Byrne Peter , Ruggiero Kenneth J , Rung Ariane , Runz Heiko , Rutten Bart P F , de Viteri Stacey Saenz , Salum Giovanni Abrahão , Sampson Laura , Sanchez Sixto E , Santoro Marcos , Seah Carina , Seedat Soraya , Seng Julia S , Shabalin Andrey , Sheerin Christina M , Silove Derrick , Smith Alicia K , Smoller Jordan W , Sponheim Scott R , Stein Dan J , Stensland Synne , Stevens Jennifer S , Sumner Jennifer A , Teicher Martin H , Thompson Wesley K , Tiwari Arun K , Trapido Edward , Uddin Monica , Ursano Robert J , Valdimarsdóttir Unnur , van den Heuvel Leigh Luella , Van Hooff Miranda , van Rooij Sanne JH , Vermetten Eric , Vinkers Christiaan H , Voisey Joanne , Wang Zhewu , Wang Yunpeng , Waszczuk Monika , Weber Heike , Wendt Frank R , Werge Thomas , Williams Michelle A , Williamson Douglas E , Winsvold Bendik S , Winternitz Sherry , Wolf Erika J , Wolf Christiane , Xia Yan , Xiong Ying , Yehuda Rachel , Young Ross McD , Young Keith A , Zai Clement C , Zai Gwyneth C , Zervas Mark , Zhao Hongyu , Zoellner Lori A , Zwart John-Anker , Stein Murray B , Ressler Kerry J , Koenen Karestan C 
Published: September 2023

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g.,GRIA1, GRM8, CACNA1E), developmental, axon guidance, and transcription factors (e.g.,FOXP2, EFNA5, DCC), synaptic structure and function genes (e.g.,PCLO, NCAM1, PDE4B), and endocrine or immune regulators (e.g.,ESR1, TRAF3, TANK). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.