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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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Related in: MedlinePlus

Functional Annotation of Transcripts Regulated by MDD-Related GR Risk Variants(A) Gene network produced using GeneMANIA. The network consists of 43 genes (circles) connected by 164 interactions (edges). Genes that are within a black filled circle indicate our MDD-related GR transcripts (n = 24), while those within a gray filled circle indicate additional genes (n = 20). The interactions found between these genes, which were more enriched than expected, are shown (co-expression: purple lines, shared protein domains: yellow lines, and co-localization: blue lines).(B) Heatmap of gene expression changes (log2) between stress versus vehicle groups of mouse in brain and blood (n = 17 mice, left panel) as well as between baseline and GR-stimulation in human blood cells (blue, middle panel) and in mouse brain and blood (n = 22 mice, right panel). Investigated tissues are labeled within the bottom row of the heatmap (prefrontal cortex [PFC], hippocampus [HC], and amygdala [AM]). p values were computed by using linear regression model, and significance is indicated by a black box (FDR ≤ 0.1, dotted box p ≤ 0.05).
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fig6: Functional Annotation of Transcripts Regulated by MDD-Related GR Risk Variants(A) Gene network produced using GeneMANIA. The network consists of 43 genes (circles) connected by 164 interactions (edges). Genes that are within a black filled circle indicate our MDD-related GR transcripts (n = 24), while those within a gray filled circle indicate additional genes (n = 20). The interactions found between these genes, which were more enriched than expected, are shown (co-expression: purple lines, shared protein domains: yellow lines, and co-localization: blue lines).(B) Heatmap of gene expression changes (log2) between stress versus vehicle groups of mouse in brain and blood (n = 17 mice, left panel) as well as between baseline and GR-stimulation in human blood cells (blue, middle panel) and in mouse brain and blood (n = 22 mice, right panel). Investigated tissues are labeled within the bottom row of the heatmap (prefrontal cortex [PFC], hippocampus [HC], and amygdala [AM]). p values were computed by using linear regression model, and significance is indicated by a black box (FDR ≤ 0.1, dotted box p ≤ 0.05).

Mentions: Next, we investigated whether the probe genes (n = 24), regulated by the MDD-related GR eSNPs, are part of specific pathways that may be relevant for the pathophysiology of psychiatric disorders. Using the GeneMANIA tool (Montojo et al., 2014), we were able to generate a gene network containing 23 of the 24 MDD-related GR genes (see Figure 6A and Experimental Procedures). Within this network, the type of interactions between the MDD-related GR genes that were most enriched were: co-expression (1.21 times the number expected when using other GR-stimulated transcript sets), co-localization (genes are expressed in the same tissue or proteins are found in the same location; fold enrichment = 1.21), and shared protein domains (fold enrichment = 3.77). Several genes, e.g., FTH1, CCT7, RPS2, IMPDH2, and PELI1, presented more than ten interactions. Additional co-expression analysis identified that the MDD-related GR genes are more tightly co-regulated in blood than in 1,000 sets of randomly chosen transcripts selected from all GR-responsive transcripts (fold enrichment = 1.04, permutation-based FDR = 0.078). These data provide support that the MDD-related GR genes functionally interact to perform an orchestrated function, i.e., they are coordinated in their transcriptional response to GR activation or stress. A limited network analysis through manually curated interactions from the scientific literature (Lechner et al., 2012) revealed that these genes show associations with MDD, SCZ, BPD, neurodevelopmental disorders, posttraumatic stress disorder, and response to antidepressant treatment in independent datasets (see Figure S3). In addition, they seem predominantly involved in pathways associated with ubiquitination and proteasome degradation and the inflammatory response, systems that have been implicated in the pathophysiology of MDD and SCZ, as well as in stress-related changes in synaptic plasticity (Miller et al., 2009; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014; Tai and Schuman, 2008).


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)

Functional Annotation of Transcripts Regulated by MDD-Related GR Risk Variants(A) Gene network produced using GeneMANIA. The network consists of 43 genes (circles) connected by 164 interactions (edges). Genes that are within a black filled circle indicate our MDD-related GR transcripts (n = 24), while those within a gray filled circle indicate additional genes (n = 20). The interactions found between these genes, which were more enriched than expected, are shown (co-expression: purple lines, shared protein domains: yellow lines, and co-localization: blue lines).(B) Heatmap of gene expression changes (log2) between stress versus vehicle groups of mouse in brain and blood (n = 17 mice, left panel) as well as between baseline and GR-stimulation in human blood cells (blue, middle panel) and in mouse brain and blood (n = 22 mice, right panel). Investigated tissues are labeled within the bottom row of the heatmap (prefrontal cortex [PFC], hippocampus [HC], and amygdala [AM]). p values were computed by using linear regression model, and significance is indicated by a black box (FDR ≤ 0.1, dotted box p ≤ 0.05).
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fig6: Functional Annotation of Transcripts Regulated by MDD-Related GR Risk Variants(A) Gene network produced using GeneMANIA. The network consists of 43 genes (circles) connected by 164 interactions (edges). Genes that are within a black filled circle indicate our MDD-related GR transcripts (n = 24), while those within a gray filled circle indicate additional genes (n = 20). The interactions found between these genes, which were more enriched than expected, are shown (co-expression: purple lines, shared protein domains: yellow lines, and co-localization: blue lines).(B) Heatmap of gene expression changes (log2) between stress versus vehicle groups of mouse in brain and blood (n = 17 mice, left panel) as well as between baseline and GR-stimulation in human blood cells (blue, middle panel) and in mouse brain and blood (n = 22 mice, right panel). Investigated tissues are labeled within the bottom row of the heatmap (prefrontal cortex [PFC], hippocampus [HC], and amygdala [AM]). p values were computed by using linear regression model, and significance is indicated by a black box (FDR ≤ 0.1, dotted box p ≤ 0.05).
Mentions: Next, we investigated whether the probe genes (n = 24), regulated by the MDD-related GR eSNPs, are part of specific pathways that may be relevant for the pathophysiology of psychiatric disorders. Using the GeneMANIA tool (Montojo et al., 2014), we were able to generate a gene network containing 23 of the 24 MDD-related GR genes (see Figure 6A and Experimental Procedures). Within this network, the type of interactions between the MDD-related GR genes that were most enriched were: co-expression (1.21 times the number expected when using other GR-stimulated transcript sets), co-localization (genes are expressed in the same tissue or proteins are found in the same location; fold enrichment = 1.21), and shared protein domains (fold enrichment = 3.77). Several genes, e.g., FTH1, CCT7, RPS2, IMPDH2, and PELI1, presented more than ten interactions. Additional co-expression analysis identified that the MDD-related GR genes are more tightly co-regulated in blood than in 1,000 sets of randomly chosen transcripts selected from all GR-responsive transcripts (fold enrichment = 1.04, permutation-based FDR = 0.078). These data provide support that the MDD-related GR genes functionally interact to perform an orchestrated function, i.e., they are coordinated in their transcriptional response to GR activation or stress. A limited network analysis through manually curated interactions from the scientific literature (Lechner et al., 2012) revealed that these genes show associations with MDD, SCZ, BPD, neurodevelopmental disorders, posttraumatic stress disorder, and response to antidepressant treatment in independent datasets (see Figure S3). In addition, they seem predominantly involved in pathways associated with ubiquitination and proteasome degradation and the inflammatory response, systems that have been implicated in the pathophysiology of MDD and SCZ, as well as in stress-related changes in synaptic plasticity (Miller et al., 2009; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014; Tai and Schuman, 2008).

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