Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood
Authors: Daskalakis Nikolaos P. , Iatrou Artemis , Chatzinakos Chris , Jajoo Aarti , Snijders Clara , Wylie Dennis , DiPietro Christopher P. , Tsatsani Ioulia , Chen Chia-Yen , Pernia Cameron D. , Soliva-Estruch Marina , Arasappan Dhivya , Bharadwaj Rahul A. , Collado-Torres Leonardo , Wuchty Stefan , Alvarez Victor E. , Dammer Eric B. , Deep-Soboslay Amy , Duong Duc M. , Eagles Nick , Huber Bertrand R. , Huuki Louise , Holstein Vincent L. , Logue Mark W. , Lugenbühl Justina F. , Maihofer Adam X. , Miller Mark W. , Nievergelt Caroline M. , Pertea Geo , Ross Deanna , Sendi Mohammad S. E. , Sun Benjamin B. , Tao Ran , Tooke James , Wolf Erika J. , Zeier Zane ,   PTSD Working Group of Psychiatric Genomics Consortium**, Berretta Sabina , Champagne Frances A. , Hyde Thomas , Seyfried Nicholas T. , Shin Joo Heon , Weinberger Daniel R. , Nemeroff Charles B. , Kleinman Joel E. , Ressler Kerry J. , Nievergelt Caroline M. , Maihofer Adam X. , Atkinson Elizabeth G. , Chen Chia-Yen , Choi Karmel W. , Coleman Jonathan R. I. , 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 , Babić 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. , Desarnaud Frank , DiPietro Christopher P. , Disner Seth G. , Docherty Anna R. , Domschke Katharina , Dyb Grete , Kulenović Alma Džubur , 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. , Goleva Slavina B. , Gordon Scott D. , Goçi Aferdita , Grasser Lana Ruvolo , Guindalini Camila , Haas Magali , Hagenaars Saskia , Hauser Michael A. , Heath Andrew C. , Hemmings Sian M. J. , Hesselbrock Victor , Hickie Ian B. , Hogan Kelleigh , Hougaard David Michael , Huang Hailiang , Huckins Laura M. , Hveem Kristian , Jakovljević 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 Alex O. , Rothbaum Barbara 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 Hooff Miranda , Vermetten Eric , Vinkers Christiaan H. , Voisey Joanne , Wang Yunpeng , Wang Zhewu , Waszczuk Monika , Weber Heike , Wendt Frank R. , Werge Thomas , Williams Michelle A. , Williamson Douglas E. , Winsvold Bendik S. , Winternitz Sherry , Wolf Christiane , Wolf Erika J. , Xia Yan , Xiong Ying , Yehuda Rachel , Young Keith A. , Young Ross McD , Zai Clement C. , Zai Gwyneth C. , Zervas Mark , Zhao Hongyu , Zoellner Lori A. , Zwart John-Anker , deRoon-Cassini Terri , van Rooij Sanne J. H. , van den Heuvel Leigh L. ,   AURORA Study,   Estonian Biobank Research Team,   FinnGen Investigators,   HUNT All-In Psychiatry, Stein Murray B. , Ressler Kerry J. , Koenen Karestan C. 
Published: May 2024

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.