Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.
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.
Affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.Show MeSH
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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.
Affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.