Limits...
Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.

Arloth J, Bogdan R, Weber P, Frishman G, Menke A, Wagner KV, Balsevich G, Schmidt MV, Karbalai N, Czamara D, Altmann A, Trümbach D, Wurst W, Mehta D, Uhr M, Klengel T, Erhardt A, Carey CE, Conley ED, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC)Ruepp A, Müller-Myhsok B, Hariri AR, Binder EB, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium P - Neuron (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.

Show MeSH

Related in: MedlinePlus

GR-Response eSNPs Are Enriched in Enhancer Regions in Multiple TissuesBar graph illustrating the enrichment of GR-response eSNPs for enhancers in multiple tissues from the Roadmap Epigenome Project, including brain tissue. The x axis shows the fold enrichment and the y axis all brain enhancers all well as the mean fold enrichment among all hematopoietic cells (see Figure S2) and brain enhancers. The fold enrichment for GR-response eSNPs is illustrated in red and for the permuted baseline eSNPs in blue. Only the GR-response eSNP enrichment, which passes a Bonferroni corrected significance threshold (corrected for the number of all tested tissues or cells, n = 62) is illustrated. ∗ p ≤ 0.05, obtained by binomial enrichment test and Bonferroni correction, error bars ± SD.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4490780&req=5

fig3: GR-Response eSNPs Are Enriched in Enhancer Regions in Multiple TissuesBar graph illustrating the enrichment of GR-response eSNPs for enhancers in multiple tissues from the Roadmap Epigenome Project, including brain tissue. The x axis shows the fold enrichment and the y axis all brain enhancers all well as the mean fold enrichment among all hematopoietic cells (see Figure S2) and brain enhancers. The fold enrichment for GR-response eSNPs is illustrated in red and for the permuted baseline eSNPs in blue. Only the GR-response eSNP enrichment, which passes a Bonferroni corrected significance threshold (corrected for the number of all tested tissues or cells, n = 62) is illustrated. ∗ p ≤ 0.05, obtained by binomial enrichment test and Bonferroni correction, error bars ± SD.

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.


Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.

Arloth J, Bogdan R, Weber P, Frishman G, Menke A, Wagner KV, Balsevich G, Schmidt MV, Karbalai N, Czamara D, Altmann A, Trümbach D, Wurst W, Mehta D, Uhr M, Klengel T, Erhardt A, Carey CE, Conley ED, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC)Ruepp A, Müller-Myhsok B, Hariri AR, Binder EB, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium P - Neuron (2015)

GR-Response eSNPs Are Enriched in Enhancer Regions in Multiple TissuesBar graph illustrating the enrichment of GR-response eSNPs for enhancers in multiple tissues from the Roadmap Epigenome Project, including brain tissue. The x axis shows the fold enrichment and the y axis all brain enhancers all well as the mean fold enrichment among all hematopoietic cells (see Figure S2) and brain enhancers. The fold enrichment for GR-response eSNPs is illustrated in red and for the permuted baseline eSNPs in blue. Only the GR-response eSNP enrichment, which passes a Bonferroni corrected significance threshold (corrected for the number of all tested tissues or cells, n = 62) is illustrated. ∗ p ≤ 0.05, obtained by binomial enrichment test and Bonferroni correction, error bars ± SD.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490780&req=5

fig3: GR-Response eSNPs Are Enriched in Enhancer Regions in Multiple TissuesBar graph illustrating the enrichment of GR-response eSNPs for enhancers in multiple tissues from the Roadmap Epigenome Project, including brain tissue. The x axis shows the fold enrichment and the y axis all brain enhancers all well as the mean fold enrichment among all hematopoietic cells (see Figure S2) and brain enhancers. The fold enrichment for GR-response eSNPs is illustrated in red and for the permuted baseline eSNPs in blue. Only the GR-response eSNP enrichment, which passes a Bonferroni corrected significance threshold (corrected for the number of all tested tissues or cells, n = 62) is illustrated. ∗ p ≤ 0.05, obtained by binomial enrichment test and Bonferroni correction, error bars ± SD.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.

Show MeSH
Related in: MedlinePlus