Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts

Autor: Anna Schneider, Sarah Wilker, Alexander Karabatsiakis, Anett Pfeiffer, Vanja Vukojevic, Andreas Papassotiropoulos, Dominique J.-F. de Quervain, Iris-Tatjana Kolassa, Stephan Kolassa, Virginie Freytag, Thomas Elbert, Christian Vogler, Daniela Conrad, Annette Milnik
Rok vydání: 2018
Předmět:
Adult
Risk
gene set enrichment analysis
0301 basic medicine
Oncology
medicine.medical_specialty
Microarray
Genetic and Epigenetic Associations with Trauma Exposure
Cognitive Neuroscience
Nerve Tissue Proteins
Experimental and Cognitive Psychology
Single-nucleotide polymorphism
Locus (genetics)
Psychological Trauma
Polymorphism
Single Nucleotide
Epigenesis
Genetic
Cohort Studies
Stress Disorders
Post-Traumatic
03 medical and health sciences
0302 clinical medicine
ddc:150
Developmental Neuroscience
Internal medicine
MAGMA
medicine
Humans
candidate gene analysis
SNP
Uganda
Epigenetics
Receptor
Notch3
Biological Psychiatry
Notch receptor processing
epigenetics
Endocrine and Autonomic Systems
General Neuroscience
Rwanda
DNA Methylation
NOTCH
030104 developmental biology
Neuropsychology and Physiological Psychology
Neurology
posttraumatic stress disorder
Notch binding
CpG Islands
Psychology
Candidate Gene Analysis
030217 neurology & neurosurgery
Signal Transduction
Zdroj: Psychophysiology
ISSN: 1469-8986
0048-5772
DOI: 10.1111/psyp.13288
Popis: The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans‐membrane receptor proteins (NOTCH1–4), constitutes an evolutionarily well‐conserved intercellular communication pathway (involved, e.g., in cell–cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1–4 (investigated by microarray) and genomic methylation of saliva‐derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N 1 = 924) and Rwanda (N 2 = 371), and investigated whether NOTCH‐related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (p uncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (p uncorrected = 0.05) in Rwandans. Yet, none of the (epi‐)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (p corrected = 0.003) and NOTCH receptor processing (p corrected = 0.01). The environmental factor trauma load was significant in all analyses (all p
Integrating genetic, epigenetic, and gene set enrichment analyses, while accounting for the environmental factor traumatic load, we identified stress‐ and memory‐associated neurogenic locus notch homolog protein (NOTCH) genes and related gene sets as potential risk mediators for the development of posttraumatic stress disorder (PTSD) after trauma. Thus, our results strengthen the presumed role of memory‐ and inflammation‐associated genes in PTSD development, and revealed a promising target for future treatment studies. Furthermore, we demonstrated the importance of traumatic load in PTSD etiology, and of an integrated approach in order to obtain a more comprehensive understanding of the functionality of PTSD‐associated markers.
Databáze: OpenAIRE
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