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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.

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GR-Response eSNPs Are Enriched among Variants Associated with MDD(A) The dotted red line shows the enriched number of GR-response eSNPs that overlap with SNPs in our meta-analysis for MDD (= MDD-related GR eSNPs; 8,864 cases and 8,982 controls). The distribution of the observed overlap for sets of 1,000 random SNPs (gray) and 1,000 random baseline eSNPs (blue) are represented as histograms ( distributions). Both permuted data sets never reached the same overlap with MDD-associated SNPs as the GR-response eSNPs.(B) The distribution of the MDD-related GR eSNP genetic risk profile scores (GRPSs) for an independent sample of MDD cases (n = 1,005 cases; red) and controls (n = 478; gray) are represented as density plots. Individuals with MDD display higher GRPSs (p = 0.00017). p value by logistic regression model.
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fig5: GR-Response eSNPs Are Enriched among Variants Associated with MDD(A) The dotted red line shows the enriched number of GR-response eSNPs that overlap with SNPs in our meta-analysis for MDD (= MDD-related GR eSNPs; 8,864 cases and 8,982 controls). The distribution of the observed overlap for sets of 1,000 random SNPs (gray) and 1,000 random baseline eSNPs (blue) are represented as histograms ( distributions). Both permuted data sets never reached the same overlap with MDD-associated SNPs as the GR-response eSNPs.(B) The distribution of the MDD-related GR eSNP genetic risk profile scores (GRPSs) for an independent sample of MDD cases (n = 1,005 cases; red) and controls (n = 478; gray) are represented as density plots. Individuals with MDD display higher GRPSs (p = 0.00017). p value by logistic regression model.

Mentions: Besides their functional characterization, an important question was to assess whether the genetic variants that alter the immediate transcriptional response to GR activation (GR-response eSNPs) would also be associated with risk for stress-related psychiatric disorder. To assess this, we first tested whether our GR-response eSNPs were overrepresented among SNPs associated with MDD in the genome-wide association study (GWAS) results of the Psychiatric Genomics Consortium (PGC), which includes approximately 9,000 cases and the same number of controls (Ripke et al., 2013). Among nominally associated loci with MDD (at meta-analysis p value ≤ 0.05), 282 SNPs also represent a GR-response eSNP. Permutation analysis (see Experimental Procedures) predicted an expected mean overlap of 210 SNPs from 1,000 randomly selected SNP sets (fold enrichment = 1.34, permutation-based FDR < 0.001; Figure 5A). We next investigated whether GR-response eSNPs were also enriched over baseline eSNPs, as SNPs associated with transcriptional changes have been shown to be more enriched in GWASs in general (Roussos et al., 2014). Again the mean overlap for 1,000 permuted baseline cis-eSNP sets (218 SNPs) was significantly lower than the actual overlap of GR-response eSNPs (fold enrichment = 1.29, permutation-based FDR < 0.001; Figure 5A). These enrichments remain significant when using only the tag eSNPs (n = 285) to control for possible confounding due to linkage disequilibrium (LD) structure (fold enrichment = 1.31, permutation-based FDR = 0.082).


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 among Variants Associated with MDD(A) The dotted red line shows the enriched number of GR-response eSNPs that overlap with SNPs in our meta-analysis for MDD (= MDD-related GR eSNPs; 8,864 cases and 8,982 controls). The distribution of the observed overlap for sets of 1,000 random SNPs (gray) and 1,000 random baseline eSNPs (blue) are represented as histograms ( distributions). Both permuted data sets never reached the same overlap with MDD-associated SNPs as the GR-response eSNPs.(B) The distribution of the MDD-related GR eSNP genetic risk profile scores (GRPSs) for an independent sample of MDD cases (n = 1,005 cases; red) and controls (n = 478; gray) are represented as density plots. Individuals with MDD display higher GRPSs (p = 0.00017). p value by logistic regression model.
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fig5: GR-Response eSNPs Are Enriched among Variants Associated with MDD(A) The dotted red line shows the enriched number of GR-response eSNPs that overlap with SNPs in our meta-analysis for MDD (= MDD-related GR eSNPs; 8,864 cases and 8,982 controls). The distribution of the observed overlap for sets of 1,000 random SNPs (gray) and 1,000 random baseline eSNPs (blue) are represented as histograms ( distributions). Both permuted data sets never reached the same overlap with MDD-associated SNPs as the GR-response eSNPs.(B) The distribution of the MDD-related GR eSNP genetic risk profile scores (GRPSs) for an independent sample of MDD cases (n = 1,005 cases; red) and controls (n = 478; gray) are represented as density plots. Individuals with MDD display higher GRPSs (p = 0.00017). p value by logistic regression model.
Mentions: Besides their functional characterization, an important question was to assess whether the genetic variants that alter the immediate transcriptional response to GR activation (GR-response eSNPs) would also be associated with risk for stress-related psychiatric disorder. To assess this, we first tested whether our GR-response eSNPs were overrepresented among SNPs associated with MDD in the genome-wide association study (GWAS) results of the Psychiatric Genomics Consortium (PGC), which includes approximately 9,000 cases and the same number of controls (Ripke et al., 2013). Among nominally associated loci with MDD (at meta-analysis p value ≤ 0.05), 282 SNPs also represent a GR-response eSNP. Permutation analysis (see Experimental Procedures) predicted an expected mean overlap of 210 SNPs from 1,000 randomly selected SNP sets (fold enrichment = 1.34, permutation-based FDR < 0.001; Figure 5A). We next investigated whether GR-response eSNPs were also enriched over baseline eSNPs, as SNPs associated with transcriptional changes have been shown to be more enriched in GWASs in general (Roussos et al., 2014). Again the mean overlap for 1,000 permuted baseline cis-eSNP sets (218 SNPs) was significantly lower than the actual overlap of GR-response eSNPs (fold enrichment = 1.29, permutation-based FDR < 0.001; Figure 5A). These enrichments remain significant when using only the tag eSNPs (n = 285) to control for possible confounding due to linkage disequilibrium (LD) structure (fold enrichment = 1.31, permutation-based FDR = 0.082).

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