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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-Modulating cis-eQTLs(A) Study design for GR-stimulated gene expression in whole blood of 160 male individuals from the Max Planck Institute of Psychiatry cohort.(B) Circularized Manhattan plot displaying cis-associations for GR-response eQTL bins (n = 320) and their respective significance (−log10 Q values). Displayed from the outer to the inner circle are the number of chromosomes, the ideograms for the human karyotype (hg18), genes nearby eSNPs, and Manhattan plots for the eQTL bins that survived correction for multiple testing.(C and D) Boxplots of human gene expression values for ADORA3, which is an example of a significant GR-response eQTL. Expression levels are stratified based on the eSNP genotypes for ADORA3. Baseline (6 p.m.) measures are displayed in blue and GR-stimulated measures (9 p.m.) in red. Microarrays data are displayed in (C) and their qPCR validation in (D). Q value in (C) is derived from GR-response cis-eQTL analysis and the p value in (D) from the qPCR linear regression model.
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fig2: GR-Response-Modulating cis-eQTLs(A) Study design for GR-stimulated gene expression in whole blood of 160 male individuals from the Max Planck Institute of Psychiatry cohort.(B) Circularized Manhattan plot displaying cis-associations for GR-response eQTL bins (n = 320) and their respective significance (−log10 Q values). Displayed from the outer to the inner circle are the number of chromosomes, the ideograms for the human karyotype (hg18), genes nearby eSNPs, and Manhattan plots for the eQTL bins that survived correction for multiple testing.(C and D) Boxplots of human gene expression values for ADORA3, which is an example of a significant GR-response eQTL. Expression levels are stratified based on the eSNP genotypes for ADORA3. Baseline (6 p.m.) measures are displayed in blue and GR-stimulated measures (9 p.m.) in red. Microarrays data are displayed in (C) and their qPCR validation in (D). Q value in (C) is derived from GR-response cis-eQTL analysis and the p value in (D) from the qPCR linear regression model.

Mentions: We first identified genetic variants that alter GR-stimulated gene expression changes by adopting a stimulated expression quantitative trait locus (eQTL) approach (Figure 2A). Gene expression profiles in peripheral blood cells from 160 male individuals of the Max-Planck Institute of Psychiatry (MPIP) cohort (91 cases and 69 controls, see Experimental Procedures) were obtained at baseline and 3 hr after stimulation with the selective GR agonist dexamethasone (Figure S1A) and combined with genome-wide SNP data. All individuals showed a strong endocrine response to dexamethasone (Cortisol: F1,159 = 43.93, p = 5.02 × 10−10 and ACTH: F1,158 = 37.96, p = 5.76 × 10−9; Figures S1B and S1C). After quality control, 4,447 gene expression probes that exhibited strong regulation following dexamethasone administration (absolute fold change in gene expression from baseline to 3 hr post-dexamethasone ≥ 1.3 in at least 20% of all samples) were combined with genotype data of ∼2 million imputed SNPs (see Experimental Procedures). Using the log fold change in gene expression standardized to baseline values as the outcome and restricting the analysis to a ± 1 Mb cis-region around each probe, we found that 3,820 GR-response-modulating cis-eQTLs (GR-response eQTLs) remained significant after accounting for disease status, age, and BMI and correction for multiple testing (see Experimental Procedures). These comprised 297 unique array probes and 3,662 unique SNPs. The 3,662 unique GR-response cis-expression SNPs (eSNPs) can be summarized in terms of independent tag SNPs into 296 uncorrelated GR-response cis-eSNP bins, i.e., sets of SNPs in linkage disequilibrium (LD; see Experimental Procedures). We defined the tag eSNP as the eSNP showing the highest association per bin (lowest Q value). These 296 GR-response cis-eSNP bins correspond to 320 GR-response cis-eQTL bins, i.e., cis-eSNP bin-probe combinations, as one cis-eSNP bin can be associated with the regulation of more than one transcript and vice versa. These GR-response cis-eQTL bins are listed in Table S1 and illustrated in Figures 2B–2D. Including dexamethasone serum levels or the blood cell count as covariate did not change the results, excluding any confounding effects of individual differences in dexamethasone concentration and cellular composition (see Supplemental Information).


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-Modulating cis-eQTLs(A) Study design for GR-stimulated gene expression in whole blood of 160 male individuals from the Max Planck Institute of Psychiatry cohort.(B) Circularized Manhattan plot displaying cis-associations for GR-response eQTL bins (n = 320) and their respective significance (−log10 Q values). Displayed from the outer to the inner circle are the number of chromosomes, the ideograms for the human karyotype (hg18), genes nearby eSNPs, and Manhattan plots for the eQTL bins that survived correction for multiple testing.(C and D) Boxplots of human gene expression values for ADORA3, which is an example of a significant GR-response eQTL. Expression levels are stratified based on the eSNP genotypes for ADORA3. Baseline (6 p.m.) measures are displayed in blue and GR-stimulated measures (9 p.m.) in red. Microarrays data are displayed in (C) and their qPCR validation in (D). Q value in (C) is derived from GR-response cis-eQTL analysis and the p value in (D) from the qPCR linear regression model.
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fig2: GR-Response-Modulating cis-eQTLs(A) Study design for GR-stimulated gene expression in whole blood of 160 male individuals from the Max Planck Institute of Psychiatry cohort.(B) Circularized Manhattan plot displaying cis-associations for GR-response eQTL bins (n = 320) and their respective significance (−log10 Q values). Displayed from the outer to the inner circle are the number of chromosomes, the ideograms for the human karyotype (hg18), genes nearby eSNPs, and Manhattan plots for the eQTL bins that survived correction for multiple testing.(C and D) Boxplots of human gene expression values for ADORA3, which is an example of a significant GR-response eQTL. Expression levels are stratified based on the eSNP genotypes for ADORA3. Baseline (6 p.m.) measures are displayed in blue and GR-stimulated measures (9 p.m.) in red. Microarrays data are displayed in (C) and their qPCR validation in (D). Q value in (C) is derived from GR-response cis-eQTL analysis and the p value in (D) from the qPCR linear regression model.
Mentions: We first identified genetic variants that alter GR-stimulated gene expression changes by adopting a stimulated expression quantitative trait locus (eQTL) approach (Figure 2A). Gene expression profiles in peripheral blood cells from 160 male individuals of the Max-Planck Institute of Psychiatry (MPIP) cohort (91 cases and 69 controls, see Experimental Procedures) were obtained at baseline and 3 hr after stimulation with the selective GR agonist dexamethasone (Figure S1A) and combined with genome-wide SNP data. All individuals showed a strong endocrine response to dexamethasone (Cortisol: F1,159 = 43.93, p = 5.02 × 10−10 and ACTH: F1,158 = 37.96, p = 5.76 × 10−9; Figures S1B and S1C). After quality control, 4,447 gene expression probes that exhibited strong regulation following dexamethasone administration (absolute fold change in gene expression from baseline to 3 hr post-dexamethasone ≥ 1.3 in at least 20% of all samples) were combined with genotype data of ∼2 million imputed SNPs (see Experimental Procedures). Using the log fold change in gene expression standardized to baseline values as the outcome and restricting the analysis to a ± 1 Mb cis-region around each probe, we found that 3,820 GR-response-modulating cis-eQTLs (GR-response eQTLs) remained significant after accounting for disease status, age, and BMI and correction for multiple testing (see Experimental Procedures). These comprised 297 unique array probes and 3,662 unique SNPs. The 3,662 unique GR-response cis-expression SNPs (eSNPs) can be summarized in terms of independent tag SNPs into 296 uncorrelated GR-response cis-eSNP bins, i.e., sets of SNPs in linkage disequilibrium (LD; see Experimental Procedures). We defined the tag eSNP as the eSNP showing the highest association per bin (lowest Q value). These 296 GR-response cis-eSNP bins correspond to 320 GR-response cis-eQTL bins, i.e., cis-eSNP bin-probe combinations, as one cis-eSNP bin can be associated with the regulation of more than one transcript and vice versa. These GR-response cis-eQTL bins are listed in Table S1 and illustrated in Figures 2B–2D. Including dexamethasone serum levels or the blood cell count as covariate did not change the results, excluding any confounding effects of individual differences in dexamethasone concentration and cellular composition (see Supplemental Information).

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