Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood-Reference-Cited by-同舟云学术

Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood

Published:2024-05-24 Issue:6698 Volume:384 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Daskalakis Nikolaos P.¹²³,Iatrou Artemis¹²³,Chatzinakos Chris¹³⁴⁵,Jajoo Aarti¹²³,Snijders Clara¹²³,Wylie Dennis⁶,DiPietro Christopher P.¹³,Tsatsani Ioulia¹²³⁷,Chen Chia-Yen⁸,Pernia Cameron D.¹²³,Soliva-Estruch Marina¹²³⁷,Arasappan Dhivya⁶,Bharadwaj Rahul A.⁹,Collado-Torres Leonardo⁹,Wuchty Stefan¹⁰¹¹,Alvarez Victor E.¹²¹³¹⁴,Dammer Eric B.¹⁵,Deep-Soboslay Amy⁹,Duong Duc M.¹⁵,Eagles Nick⁹,Huber Bertrand R.¹²¹⁴,Huuki Louise⁹,Holstein Vincent L.¹²³,Logue Mark W.¹⁶¹⁷¹⁸¹⁹,Lugenbühl Justina F.¹²³⁷,Maihofer Adam X.²⁰²¹²²,Miller Mark W.¹⁶¹⁷,Nievergelt Caroline M.²⁰²¹²²,Pertea Geo⁹,Ross Deanna²³,Sendi Mohammad S. E.¹²³,Sun Benjamin B.⁸,Tao Ran⁹,Tooke James⁹,Wolf Erika J.¹⁶¹⁷,Zeier Zane²⁴, ,Berretta Sabina¹²³,Champagne Frances A.²³,Hyde Thomas⁹²⁵²⁶,Seyfried Nicholas T.¹⁵,Shin Joo Heon⁹²⁶,Weinberger Daniel R.⁹²⁵²⁶²⁷²⁸,Nemeroff Charles B.²³²⁹,Kleinman Joel E.⁹²⁵,Ressler Kerry J.¹²,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., , , , ,Stein Murray B.,Ressler Kerry J.,Koenen Karestan C.

Affiliation:

1. McLean Hospital, Belmont, MA 02478, USA.

2. Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA.

3. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

4. Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY 11203, USA.

5. VA New York Harbor Healthcare System, Brooklyn, NY 11209, USA.

6. Center for Biomedical Research Support, The University of Texas at Austin, Austin, TX 78712, USA.

7. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, 6229 ER, Netherlands.

8. Biogen Inc., Cambridge, MA 02142, USA.

9. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA.

10. Departments of Computer Science, University of Miami, Miami, FL 33146, USA.

11. Department of Biology, University of Miami, Miami, FL 33146, USA.

12. Department of Neurology, Boston University, Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.

13. VA Bedford Healthcare System, Bedford, MA 01730, USA.

14. National Posttraumatic Stress Disorder Brain Bank, VA Boston Healthcare System, Boston, MA 02130, USA.

15. Department of Biochemistry, Center for Neurodegenerative Disease, Emory School of Medicine, Atlanta GA 30329, USA.

16. National Center for PTSD, VA Boston Healthcare System, Boston, MA 02130, USA.

17. Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.

18. Department of Biomedical Genetics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.

19. Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.

20. Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.

21. Center for Excellence in Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.

22. Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.

23. Department of Psychology, University of Texas at Austin, Austin, TX 78712, USA.

24. Department of Psychiatry & Behavioral Sciences, Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

25. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine; Baltimore, MD, 21205, USA.

26. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

27. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

28. Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

29. Department of Psychiatry and Behavioral Sciences, University of Texas at Austin, Austin, TX 78712, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adh3707

Reference150 articles.

1. The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

2. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

3. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

4. Minimal phenotyping yields genome-wide association signals of low specificity for major depression

5. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions

Cited by 2 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. Glucocorticoid hormone as regulator and readout of resilience;Current Opinion in Behavioral Sciences;2024-10

2. Transcriptomic analysis of the human habenula in schizophrenia;2024-02-27