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

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...

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Published inScience (American Association for the Advancement of Science) Vol. 384; no. 6698; p. eadh3707
Main 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, 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., Atkinson, Elizabeth G., Choi, Karmel W., Coleman, Jonathan R. I., 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, 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.
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 24.05.2024
Subjects
Amygdala
Amygdala - metabolism
Biomarkers
Biomarkers - metabolism
Blood
Blood plasma
Brain
Brain - metabolism
Brain mapping
Children
Chromosome Mapping
Dentate gyrus
Depressive Disorder, Major - genetics
DNA methylation
Epigenetics
Exons
Female
Gene expression
Gene mapping
Gene Regulatory Networks
Gene sequencing
Genes
Genetic Loci
Genetics
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genomics
Health risk assessment
Hippocampus
Humans
Life span
Male
Mental depression
Mental disorders
Network analysis
Neurons - metabolism
Nuclei (cytology)
Post traumatic stress disorder
Posttraumatic Stress Disorder
Prefrontal cortex
Prefrontal Cortex - metabolism
Proteins
Proteomics
Psychological stress
Risk
Sex differences
Signal transduction
Single-Cell Gene Expression Analysis
snRNA
Stat3 protein
Stress Disorders, Post-Traumatic - genetics
Suicide
Systems Biology
Transcription factors
Transcriptomics
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Summary: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.
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Writing – review & editing: N.P.D., A.I., A.J., C.S., K.J.R. with contributions from D.W., I.T., C.D.P., M.S.E., and critical input from all authors.
These authors contributed equally to this work in alphabetic order collaborators and affiliations are listed in the supplementary materials.
Resources and Data curation: N.P.D., C.S., L.C-T., A.D-S., A.X.M., C.M.N., B.B.S. Methodology N.P.D., A.I., A.J., D.W.
Supervision: N.P.D., FAC, NTS, JHS, C.B.N., J.E.K., K.J.R.
Conceptualization: N.P.D., C.B.N., J.E.K., K.J.R.
Project administration: N.P.D., C.B.N., J.E.K., K.J.R.
Investigation: N.P.D., C.C., B.A.B., D.A., A.D-S., D.M.D., R.T., J.T., S.B., F.A.C., T.H., N.T.S., J.H.S., D.R.W., C.B.N., J.E.K., K.J.R.
Writing – original draft preparation: N.P.D., A.I., A.J., C.S., K.J.R. with contributions from D.W., I.T., C.D.P., M.S-E., J.F.L. and critical input from all authors.
Project funding acquisition: N.P.D., C.B.N., J.E.K., K.J.R.
Data Preprocessing: N.P.D., A.I., C.C., A.J., C.P.D., I.T., D.A., L.C-T., E.B.D., D.M.D., N.E., G.P., Formal Analysis and Software was performed by N.P.D., A.I., C.C., A.J., D.W., C.P.D., I.T., C-Y.C. with contributions by C.S., C.D.P., M.S.E., V.H., M.S.E.S. and critical input from D.A., B.A.B., L.C-T., S.W., D.R.W., C.B.N., J.E.K., Visualization: N.P.D., A.I., C.C., A.J., C.S., D.W., with contributions C.P.D., I.T., C.D.P., M.S.E., L.C-T., L.H., J.F.L.
These authors contributed equally to this work
These authors contributed equally to this work in alphabetic order
Print summary – original draft: N.P.D., and AI with input from K.J.R.
Author Contributions
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.adh3707