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Author Notes:

Correspondence: binder@psych.mpg.de

We thank D. Spengler, A. Hoffmann, M. Rex-Haffner, S. Darchinger, A. Löschner, and M. Ködel for excellent technical support. We are grateful to S. Röh for processing the NR3C1 ChIP-seq data. We also thank L. Preis and A. Eichelkraut for recruitment and sample ascertainment of the Max-Planck Institute of Psychiatry (MPIP) cohort and Y.S. Nikolova, A.X. Gorka, B. Brigidi, K. Faig, S. Jacobson, and A. Knodt for assistance with DNS cohort data collection.

See Supplemental Information for the full list of collaborators of the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC).

Data from the human gene expression microarray experiment were deposited at the GEO repository under GEO: GSE46743.


Research Funding:

This study has received its main financial support from the European Union under European Research Council GA no. 281338 (to E.B.B.).

It was also supported by the Helmholtz Portfolio Theme ‘Metabolic Dysfunction and Common Disease’, the Helmholtz Portfolio Theme ‘Supercomputing and Modelling for the Human Brain’ (SMHB), and the BMBF through the Integrated Network IntegraMent under the auspices of the e:Med Programme (to W.W.).

J.A. was supported in part by the NeuroNova gGmbH, A.R.H. by NIH (NIDA R01-DA031579), R.B. by the Klingenstein Third Generation Foundation and McDonnell Center for Systems Neuroscience, and C.E.C. by an NSF pre-doctoral grant (DGE-1143954).

The Duke Neurogenetics Study (DNS) is supported by Duke University and the NIH (NIDA R01-DA033369).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology

Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

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Journal Title:



Volume 86, Number 5


, Pages 1189-1202

Type of Work:

Article | Final Publisher PDF


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 in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain.

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© 2015 The Authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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