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Genetic differences in the immediate transcriptome response to stress predict risk-related brain function and psychiatric disorders

Arloth, Janine, Bogdan, Ryan, Weber, Peter, Frishman, Goar, Menke, Andreas, Wagner, Klaus V., Balsevich, Georgia, Schmidt, Mathias V., Karbalai, Nazanin, Czamara, Darina, Altmann, Andre, Trümbach, Dietrich, Wurst, Wolfgang, Mehta, Divya, Uhr, Manfred, Klengel, Torsten, Erhardt, Angelika, Carey, Caitlin E., Conley, Emily Drabant, Ruepp, Andreas, Müller-Myhsok, Bertram, Hariri, Ahmad R., Binder, Elisabeth B. and O'Donovan, Michael Conlon ORCID: 2015. Genetic differences in the immediate transcriptome response to stress predict risk-related brain function and psychiatric disorders. Neuron 86 (5) , pp. 1189-1202. 10.1016/j.neuron.2015.05.034

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Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Publisher: Elsevier
ISSN: 0896-6273
Date of Acceptance: 13 May 2015
Last Modified: 31 Oct 2022 09:32

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