Journal
NEURON
Volume 86, Issue 5, Pages 1189-1202Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2015.05.034
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Funding
- European Union under European Research Council GA [281338]
- BMBF within the Program for Medical Genome Research [FKZ 01GS08151]
- DFG within the Cooperation Clinical Group Molecular Neurogenetics [WU 164/3-2]
- Helmholtz Alliance of Systems Biology [HA-215]
- Helmholtz Alliance of Mental Health in an Ageing Society [HA-215]
- NeuroNova gGmbH
- NIH [NIDA R01-DA031579, NIDA R01-DA033369]
- Klingenstein Third Generation Foundation
- McDonnell Center for Systems Neuroscience
- NSF [DGE-1143954]
- Duke University
- MRC [G0800509] Funding Source: UKRI
- Lundbeck Foundation [R155-2014-1724] Funding Source: researchfish
- Medical Research Council [MR/L010305/1, G0800509] Funding Source: researchfish
- European Research Council (ERC) [281338] Funding Source: European Research Council (ERC)
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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.
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