hide
Free keywords:
-
Abstract:
Depression risk is exacerbated by genetic factors and stress exposure;
however, the biological mechanisms through which these factors interact
to confer depression risk are poorly understood. 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. These functional genetic variants
increase risk for depression and co-heritable psychiatric disorders.
Moreover, these risk variants are associated with inappropriate amygdala
reactivity, a transdiagnostic psychiatric endophenotype and an important
stress hormone response trigger. Network modeling and animal experiments
suggest that these genetic differences inGR-induced transcriptional
activation may mediate the risk for depression and other psychiatric
disorders by alteringa network of functionally related stress-sensitive
genes in blood and brain.
