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

Nikolaos P Daskalakis; Artemis Iatrou; Chris Chatzinakos; Aarti Jajoo; Clara Snijders; Dennis Wylie; Christopher P DiPietro; Ioulia Tsatsani; Chia-Yen Chen; Cameron D Pernia; Marina Soliva-Estruch; Dhivya Arasappan; Rahul A Bharadwaj; Leonardo Collado-Torres; Stefan Wuchty; Victor E Alvarez; Eric B Dammer; Amy Deep-Soboslay; Duc M Duong; Nick Eagles; Bertrand R Huber; Louise Huuki; Vincent L Holstein; Mark W Logue; Justina F Lugenbühl; Adam X Maihofer; Mark W Miller; Caroline M Nievergelt; Geo Pertea; Deanna Ross; Mohammad S E Sendi; Benjamin B Sun; Ran Tao; James Tooke; Erika J Wolf; Zane Zeier; Sabina Berretta; Frances A Champagne; Thomas Hyde; Nicholas T Seyfried; Joo Heon Shin; Daniel R Weinberger; Charles B Nemeroff; Joel E Kleinman; Kerry J Ressler; PTSD Working Group of Psychiatric Genomics Consortium**

doi:10.1126/science.adh3707

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

Nikolaos P Daskalakis, Artemis Iatrou, Chris Chatzinakos, Aarti Jajoo, Clara Snijders, Dennis Wylie, Christopher P DiPietro, Ioulia Tsatsani, Chia-Yen Chen, Cameron D Pernia, Marina Soliva-Estruch, Dhivya Arasappan, Rahul A Bharadwaj, Leonardo Collado-Torres, Stefan Wuchty, Victor E Alvarez, Eric B Dammer, Amy Deep-Soboslay, Duc M Duong, Nick EaglesBertrand R Huber, Louise Huuki, Vincent L Holstein, Mark W Logue, Justina F Lugenbühl, Adam X Maihofer, Mark W Miller, Caroline M Nievergelt, Geo Pertea, Deanna Ross, Mohammad S E Sendi, Benjamin B Sun, Ran Tao, James Tooke, Erika J Wolf, Zane Zeier, Sabina Berretta, Frances A Champagne, Thomas Hyde, Nicholas T Seyfried, Joo Heon Shin, Daniel R Weinberger, Charles B Nemeroff, Joel E Kleinman, Kerry J Ressler, PTSD Working Group of Psychiatric Genomics Consortium**

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

7 Citations (Scopus)

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.

Original language	English
Article number	eadh3707
Journal	Science
Volume	384
Issue	6698
Number of pages	17
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.adh3707
Publication status	Published - May 2024

Keywords

Humans
Depressive Disorder, Major/genetics
Stress Disorders, Post-Traumatic/genetics
Genome-Wide Association Study
Prefrontal Cortex/metabolism
Systems Biology
Male
Brain
Female
Adult
Gene Regulatory Networks
Middle Aged
Neurons/metabolism
Biomarkers/blood
Amygdala

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10.1126/science.adh3707

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Daskalakis, N. P., Iatrou, A., Chatzinakos, C., Jajoo, A., Snijders, C., Wylie, D., DiPietro, C. P., Tsatsani, I., Chen, C.-Y., Pernia, C. D., Soliva-Estruch, M., Arasappan, D., Bharadwaj, R. A., Collado-Torres, L., Wuchty, S., Alvarez, V. E., Dammer, E. B., Deep-Soboslay, A., Duong, D. M., ... PTSD Working Group of Psychiatric Genomics Consortium** (2024). Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood. Science, 384(6698), Article eadh3707. https://doi.org/10.1126/science.adh3707

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

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.",

keywords = "Humans, Depressive Disorder, Major/genetics, Stress Disorders, Post-Traumatic/genetics, Genome-Wide Association Study, Prefrontal Cortex/metabolism, Systems Biology, Male, Brain, Female, Adult, Gene Regulatory Networks, Middle Aged, Neurons/metabolism, Biomarkers/blood, Amygdala",

author = "Daskalakis, {Nikolaos P} and Artemis Iatrou and Chris Chatzinakos and Aarti Jajoo and Clara Snijders and Dennis Wylie and DiPietro, {Christopher P} and Ioulia Tsatsani and Chia-Yen Chen and Pernia, {Cameron D} and Marina Soliva-Estruch and Dhivya Arasappan and Bharadwaj, {Rahul A} and Leonardo Collado-Torres and Stefan Wuchty and Alvarez, {Victor E} and Dammer, {Eric B} and Amy Deep-Soboslay and Duong, {Duc M} and Nick Eagles and Huber, {Bertrand R} and Louise Huuki and Holstein, {Vincent L} and Logue, {Mark W} and Lugenb{\"u}hl, {Justina F} and Maihofer, {Adam X} and Miller, {Mark W} and Nievergelt, {Caroline M} and Geo Pertea and Deanna Ross and Sendi, {Mohammad S E} and Sun, {Benjamin B} and Ran Tao and James Tooke and Wolf, {Erika J} and Zane Zeier and Sabina Berretta and Champagne, {Frances A} and Thomas Hyde and Seyfried, {Nicholas T} and Shin, {Joo Heon} and Weinberger, {Daniel R} and Nemeroff, {Charles B} and Kleinman, {Joel E} and Ressler, {Kerry J} and {PTSD Working Group of Psychiatric Genomics Consortium**} and Mortensen, {Preben Bo} and Ole Mors and Anders B{\o}rglum",

year = "2024",

month = may,

doi = "10.1126/science.adh3707",

language = "English",

volume = "384",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6698",

}

Daskalakis, NP, Iatrou, A, Chatzinakos, C, Jajoo, A, Snijders, C, Wylie, D, DiPietro, CP, Tsatsani, I, Chen, C-Y, Pernia, CD, Soliva-Estruch, M, Arasappan, D, Bharadwaj, RA, Collado-Torres, L, Wuchty, S, Alvarez, VE, Dammer, EB, Deep-Soboslay, A, Duong, DM, Eagles, N, Huber, BR, Huuki, L, Holstein, VL, Logue, MW, Lugenbühl, JF, Maihofer, AX, Miller, MW, Nievergelt, CM, Pertea, G, Ross, D, Sendi, MSE, Sun, BB, Tao, R, Tooke, J, Wolf, EJ, Zeier, Z, Berretta, S, Champagne, FA, Hyde, T, Seyfried, NT, Shin, JH, Weinberger, DR, Nemeroff, CB, Kleinman, JE, Ressler, KJ & PTSD Working Group of Psychiatric Genomics Consortium** 2024, 'Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood', Science, vol. 384, no. 6698, eadh3707. https://doi.org/10.1126/science.adh3707

TY - JOUR

T1 - Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood

AU - Daskalakis, Nikolaos P

AU - Iatrou, Artemis

AU - Chatzinakos, Chris

AU - Jajoo, Aarti

AU - Snijders, Clara

AU - Wylie, Dennis

AU - DiPietro, Christopher P

AU - Tsatsani, Ioulia

AU - Chen, Chia-Yen

AU - Pernia, Cameron D

AU - Soliva-Estruch, Marina

AU - Arasappan, Dhivya

AU - Bharadwaj, Rahul A

AU - Collado-Torres, Leonardo

AU - Wuchty, Stefan

AU - Alvarez, Victor E

AU - Dammer, Eric B

AU - Deep-Soboslay, Amy

AU - Duong, Duc M

AU - Eagles, Nick

AU - Huber, Bertrand R

AU - Huuki, Louise

AU - Holstein, Vincent L

AU - Logue, Mark W

AU - Lugenbühl, Justina F

AU - Maihofer, Adam X

AU - Miller, Mark W

AU - Nievergelt, Caroline M

AU - Pertea, Geo

AU - Ross, Deanna

AU - Sendi, Mohammad S E

AU - Sun, Benjamin B

AU - Tao, Ran

AU - Tooke, James

AU - Wolf, Erika J

AU - Zeier, Zane

AU - Berretta, Sabina

AU - Champagne, Frances A

AU - Hyde, Thomas

AU - Seyfried, Nicholas T

AU - Shin, Joo Heon

AU - Weinberger, Daniel R

AU - Nemeroff, Charles B

AU - Kleinman, Joel E

AU - Ressler, Kerry J

AU - PTSD Working Group of Psychiatric Genomics Consortium

AU - Mortensen, Preben Bo

AU - Mors, Ole

AU - Børglum, Anders

PY - 2024/5

Y1 - 2024/5

N2 - 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.

AB - 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.

KW - Humans

KW - Depressive Disorder, Major/genetics

KW - Stress Disorders, Post-Traumatic/genetics

KW - Genome-Wide Association Study

KW - Prefrontal Cortex/metabolism

KW - Systems Biology

KW - Male

KW - Brain

KW - Female

KW - Adult

KW - Gene Regulatory Networks

KW - Middle Aged

KW - Neurons/metabolism

KW - Biomarkers/blood

KW - Amygdala

UR - http://www.scopus.com/inward/record.url?scp=85194126108&partnerID=8YFLogxK

U2 - 10.1126/science.adh3707

DO - 10.1126/science.adh3707

M3 - Journal article

C2 - 38781393

SN - 0036-8075

VL - 384

JO - Science

JF - Science

IS - 6698

M1 - eadh3707

ER -

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

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Keywords

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