Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
05
10
2020
accepted:
26
03
2021
revised:
26
02
2021
pubmed:
9
5
2021
medline:
27
1
2022
entrez:
8
5
2021
Statut:
ppublish
Résumé
Posttraumatic stress disorder (PTSD) is a debilitating syndrome with substantial morbidity and mortality that occurs in the aftermath of trauma. Symptoms of major depressive disorder (MDD) are also a frequent consequence of trauma exposure. Identifying novel risk markers in the immediate aftermath of trauma is a critical step for the identification of novel biological targets to understand mechanisms of pathophysiology and prevention, as well as the determination of patients most at risk who may benefit from immediate intervention. Our study utilizes a novel approach to computationally integrate blood-based transcriptomics, genomics, and interactomics to understand the development of risk vs. resilience in the months following trauma exposure. In a two-site longitudinal, observational prospective study, we assessed over 10,000 individuals and enrolled >700 subjects in the immediate aftermath of trauma (average 5.3 h post-trauma (range 0.5-12 h)) in the Grady Memorial Hospital (Atlanta) and Jackson Memorial Hospital (Miami) emergency departments. RNA expression data and 6-month follow-up data were available for 366 individuals, while genotype, transcriptome, and phenotype data were available for 297 patients. To maximize our power and understanding of genes and pathways that predict risk vs. resilience, we utilized a set-cover approach to capture fluctuations of gene expression of PTSD or depression-converting patients and non-converting trauma-exposed controls to find representative sets of disease-relevant dysregulated genes. We annotated such genes with their corresponding expression quantitative trait loci and applied a variant of a current flow algorithm to identify genes that potentially were causal for the observed dysregulation of disease genes involved in the development of depression and PTSD symptoms after trauma exposure. We obtained a final list of 11 driver causal genes related to MDD symptoms, 13 genes for PTSD symptoms, and 22 genes in PTSD and/or MDD. We observed that these individual or combined disorders shared ESR1, RUNX1, PPARA, and WWOX as driver causal genes, while other genes appeared to be causal driver in the PTSD only or MDD only cases. A number of these identified causal pathways have been previously implicated in the biology or genetics of PTSD and MDD, as well as in preclinical models of amygdala function and fear regulation. Our work provides a promising set of initial pathways that may underlie causal mechanisms in the development of PTSD or MDD in the aftermath of trauma.
Identifiants
pubmed: 33963278
doi: 10.1038/s41380-021-01084-3
pii: 10.1038/s41380-021-01084-3
doi:
Types de publication
Journal Article
Multicenter Study
Observational Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3077-3092Subventions
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH094757
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH094759
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD085850
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002378
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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