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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

Conrad, Daniela and Wilker, Sarah and Schneider, Anna and Karabatsiakis, Alexander and Pfeiffer, Anett and Kolassa, Stephan and Freytag, Virginie and Vukojevic, Vanja and Vogler, Christian and Milnik, Annette and Papassotiropoulos, Andreas and J.-F de Quervain, Dominique and Elbert, Thomas and Kolassa, Iris-Tatjana. (2018) 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. Psychophysiology. e13288.

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Official URL: https://edoc.unibas.ch/66831/

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Abstract

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 < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.
Faculties and Departments:03 Faculty of Medicine > Bereich Psychiatrie (Klinik) > Erwachsenenpsychiatrie UPK > Molekulare Neurowissenschaften (Papassotiropoulos)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Psychiatrie (Klinik) > Erwachsenenpsychiatrie UPK > Molekulare Neurowissenschaften (Papassotiropoulos)
05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Life Sciences Training Facility (Papassotiropoulos)
07 Faculty of Psychology > Departement Psychologie > Forschungsbereich Klinische Psychologie und Neurowissenschaften > Molecular Psychology (Papassotiropoulos)
UniBasel Contributors:Papassotiropoulos, Andreas
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:0048-5772
e-ISSN:1469-8986
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:28 Nov 2018 17:01
Deposited On:28 Nov 2018 17:01

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