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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 MDD-Related eSNP GRPS Correlate with Overgeneralized Amygdala Reactivity(A) Statistical parametric map illustrating left centromedial amygdala reactivity to facial expressions with an “Angry & Fearful > Neutral” contrast in the entire sample (15 contiguous voxels; max voxel MNI coordinate, x = −24, y = −10, z = −14, t = 4.35, p = 7.76 × 10−6).(B) Higher MDD-related GR eSNP genetic risk profile scores (GRPSs) in the European-American subsample of the DNS cohort (n = 306) predicted amygdala reactivity to threat-related facial expressions in comparison to neutral facial expressions.(C and D) Post hoc analyses revealed that GRPSs did not predict amygdala reactivity to threat-related expressions (C), but that higher GRPSs predicted elevated amygdala reactivity to neutral facial expressions (D) in comparison to non-face control stimuli. The 95% confidence interval is displayed as gray shaded band in (B)–(D).
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fig7: GR-Response MDD-Related eSNP GRPS Correlate with Overgeneralized Amygdala Reactivity(A) Statistical parametric map illustrating left centromedial amygdala reactivity to facial expressions with an “Angry & Fearful > Neutral” contrast in the entire sample (15 contiguous voxels; max voxel MNI coordinate, x = −24, y = −10, z = −14, t = 4.35, p = 7.76 × 10−6).(B) Higher MDD-related GR eSNP genetic risk profile scores (GRPSs) in the European-American subsample of the DNS cohort (n = 306) predicted amygdala reactivity to threat-related facial expressions in comparison to neutral facial expressions.(C and D) Post hoc analyses revealed that GRPSs did not predict amygdala reactivity to threat-related expressions (C), but that higher GRPSs predicted elevated amygdala reactivity to neutral facial expressions (D) in comparison to non-face control stimuli. The 95% confidence interval is displayed as gray shaded band in (B)–(D).

Mentions: To investigate the relationship between MDD-related GR eSNPs and variability in stress-related brain function in humans, we applied an imaging genetics strategy to data from 647 participants (171 individuals with current or past DSM-IV Axis I disorders and 476 controls; 306 of participants were self-reported European-Americans [EUR-AM]; Table S5 and see also Experimental Procedures) of the Duke Neurogenetics Study (DNS) (see Experimental Procedures). Our analyses focused on centromedial amygdala reactivity to canonical threat-related angry and fearful facial expressions (Figure 7A), because this phenotype is clearly implicated in the etiology and pathophysiology of stress-related disorders, including depression (Phillips et al., 2003). Moreover, amygdala reactivity can trigger rapid physiological and behavioral responses to threat, including activation of the stress hormone response via projections from the medial division of the central nucleus of the amygdala, (captured in our analysis by our centromedial amygdala region of interest) to the paraventricular nucleus of the hypothalamus (Ulrich-Lai and Herman, 2009). Lastly, amygdala function is influenced by the slow-acting, presumably genomic effects of hydrocortisone administration (Henckens et al., 2010), further highlighting its importance as a systems-level phenotype sensitive to our observed GR-induced transcriptional responses.


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 MDD-Related eSNP GRPS Correlate with Overgeneralized Amygdala Reactivity(A) Statistical parametric map illustrating left centromedial amygdala reactivity to facial expressions with an “Angry & Fearful > Neutral” contrast in the entire sample (15 contiguous voxels; max voxel MNI coordinate, x = −24, y = −10, z = −14, t = 4.35, p = 7.76 × 10−6).(B) Higher MDD-related GR eSNP genetic risk profile scores (GRPSs) in the European-American subsample of the DNS cohort (n = 306) predicted amygdala reactivity to threat-related facial expressions in comparison to neutral facial expressions.(C and D) Post hoc analyses revealed that GRPSs did not predict amygdala reactivity to threat-related expressions (C), but that higher GRPSs predicted elevated amygdala reactivity to neutral facial expressions (D) in comparison to non-face control stimuli. The 95% confidence interval is displayed as gray shaded band in (B)–(D).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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fig7: GR-Response MDD-Related eSNP GRPS Correlate with Overgeneralized Amygdala Reactivity(A) Statistical parametric map illustrating left centromedial amygdala reactivity to facial expressions with an “Angry & Fearful > Neutral” contrast in the entire sample (15 contiguous voxels; max voxel MNI coordinate, x = −24, y = −10, z = −14, t = 4.35, p = 7.76 × 10−6).(B) Higher MDD-related GR eSNP genetic risk profile scores (GRPSs) in the European-American subsample of the DNS cohort (n = 306) predicted amygdala reactivity to threat-related facial expressions in comparison to neutral facial expressions.(C and D) Post hoc analyses revealed that GRPSs did not predict amygdala reactivity to threat-related expressions (C), but that higher GRPSs predicted elevated amygdala reactivity to neutral facial expressions (D) in comparison to non-face control stimuli. The 95% confidence interval is displayed as gray shaded band in (B)–(D).
Mentions: To investigate the relationship between MDD-related GR eSNPs and variability in stress-related brain function in humans, we applied an imaging genetics strategy to data from 647 participants (171 individuals with current or past DSM-IV Axis I disorders and 476 controls; 306 of participants were self-reported European-Americans [EUR-AM]; Table S5 and see also Experimental Procedures) of the Duke Neurogenetics Study (DNS) (see Experimental Procedures). Our analyses focused on centromedial amygdala reactivity to canonical threat-related angry and fearful facial expressions (Figure 7A), because this phenotype is clearly implicated in the etiology and pathophysiology of stress-related disorders, including depression (Phillips et al., 2003). Moreover, amygdala reactivity can trigger rapid physiological and behavioral responses to threat, including activation of the stress hormone response via projections from the medial division of the central nucleus of the amygdala, (captured in our analysis by our centromedial amygdala region of interest) to the paraventricular nucleus of the hypothalamus (Ulrich-Lai and Herman, 2009). Lastly, amygdala function is influenced by the slow-acting, presumably genomic effects of hydrocortisone administration (Henckens et al., 2010), further highlighting its importance as a systems-level phenotype sensitive to our observed GR-induced transcriptional responses.

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