Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.
Bottom Line: 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.Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger.
Affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.Show MeSH
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Mentions: To determine the regulatory potential of GR-response eSNPs, we investigated whether they are enriched within enhancer regions as defined by the Roadmap Epigenome Project (Kundaje et al., 2015) (see Experimental Procedures). GR-response tag eSNPs were significantly enriched within enhancers in 62 different tissues, including blood cells, but also non-hematopoietic tissue such as brain (see Figure S2). When testing baseline tag eSNPs, we only observed an enrichment in enhancers in 54% of these 62 tissues. Whether combined enrichment of both GR-response tag eSNPs and baseline tag eSNPs was observed seemed to be tissue specific (see Figure S2). In fact, GR-response eSNPs were more enriched in brain enhancers than baseline eSNPs, i.e., only one of the eight brain enhancers significantly enriched with GR-response eSNPs also displayed a significant enrichment for baseline eSNPs (see Figure 3). In contrast, we observed equal enrichment for GR-response as well as baseline eSNPs in primary hematopoietic tissues (see Figure S2). These results further support the viewpoint that GR-response eSNPs affect different transcriptional regulators than baseline eSNPs and suggest possible cross-tissue effects of these SNPs.
Affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.