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: Consistent with this model, dysfunction of GR-mediated negative feedback has been reported in MDD (de Kloet et al., 2005) as well as in individuals exposed to early adversity (Heim and Binder, 2012; Wilkinson and Goodyer, 2011), one of the strongest risk factors for the development of MDD. Moreover, genetic variation in pathways regulating GR signaling has been linked with MDD risk (van Rossum et al., 2006). Here, we show that common genetic variants that modulate the initial transcriptional response to GR activation increase the risk for MDD as well as other psychiatric disorders. Gene network modeling and animal experiments suggest that these genetic differences in the transcriptional response to GR activation may mediate risk for depression and other psychiatric disorders by altering a network of co-expressed genes that are responsive to stress and glucocorticoids in the brain. In addition, these genetic variants shape the response of the amygdala, which is itself an important trigger of the stress hormone response and a functional neural phenotype implicated in the etiology and pathophysiology of depression and other forms of psychopathology (Jankord and Herman, 2008; Phillips et al., 2003). The main hypotheses and the experimental approach are summarized in Figure 1.
Affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.