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

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2020
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Wilker, Sarah
Karabatsiakis, Alexander
Kolassa, Stephan
Freytag, Virginie
Vukojevic, Vanja
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Psychophysiology. Wiley. 2020, 57(1), e13288. ISSN 0048-5772. eISSN 1469-8986. Available under: doi: 10.1111/psyp.13288
Zusammenfassung

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 (N1 = 924) and Rwanda (N2 = 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) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 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 (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 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.

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ISO 690CONRAD, Daniela, Sarah WILKER, Anna SCHNEIDER, Alexander KARABATSIAKIS, Anett PFEIFFER, Stephan KOLASSA, Virginie FREYTAG, Vanja VUKOJEVIC, Thomas ELBERT, Iris-Tatjana KOLASSA, 2020. 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. In: Psychophysiology. Wiley. 2020, 57(1), e13288. ISSN 0048-5772. eISSN 1469-8986. Available under: doi: 10.1111/psyp.13288
BibTex
@article{Conrad2020-01Integ-44343,
  year={2020},
  doi={10.1111/psyp.13288},
  title={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},
  number={1},
  volume={57},
  issn={0048-5772},
  journal={Psychophysiology},
  author={Conrad, Daniela and Wilker, Sarah and Schneider, Anna and Karabatsiakis, Alexander and Pfeiffer, Anett and Kolassa, Stephan and Freytag, Virginie and Vukojevic, Vanja and Elbert, Thomas and Kolassa, Iris-Tatjana},
  note={Article Number: e13288}
}
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    <dcterms:abstract xml:lang="eng">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 (N1 = 924) and Rwanda (N&lt;sub&gt;2&lt;/sub&gt; = 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&lt;sub&gt;uncorrected&lt;/sub&gt; = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (p&lt;sub&gt;uncorrected&lt;/sub&gt; = 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&lt;sub&gt;corrected&lt;/sub&gt; = 0.003) and NOTCH receptor processing (p&lt;sub&gt;corrected&lt;/sub&gt; = 0.01). The environmental factor trauma load was significant in all analyses (all p &lt; 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.</dcterms:abstract>
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