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

• Type of Material: Article
• Authors: Janine Arloth, Max Planck Institute of Psychiatry; Ryan Bogdan, Washington University in St. Louis; Peter Weber, Max Planck Institute of Psychiatry; Goar Frishman, German Research Center for Environmental Health; Andreas Menke, Max Planck Institute of Psychiatry; Klaus V. Wagner, Max Planck Institute of Psychiatry; Georgia Balsevich, Max Planck Institute of Psychiatry; Mathias V. Schmidt, Max Planck Institute of Psychiatry; Nazanin Karbalai, Max Planck Institute of Psychiatry; Darina Czamara, Max Planck Institute of Psychiatry; Andre Altmann, Stanford University; Dietrich Trümbach, German Research Center for Environmental Health; Wolfgang Wurst, Max Planck Institute of Psychiatry; Divya Mehta, Max Planck Institute of Psychiatry; Manfred Uhr, Max Planck Institute of Psychiatry; Torsten Klengel, Emory University; Angelika Erhardt, Max Planck Institute of Psychiatry; Caitlin E. Carey, Washington University in St. Louis; Emily Drabant Conley, 23andMe; Major Depressive Disorder Working Group, Psychiatric Genomics Consortium (PGC); Andreas Ruepp, German Research Center for Environmental Health; Bertram Müller-Myhsok, Max Planck Institute of Psychiatry; Ahmad R. Hariri, Duke University; Elisabeth Binder, Emory University
• Language: English
• Date: 2015-06-03
• Publisher: Elsevier (Cell Press)
• Publication Version: Final Published Version
• Copyright Statement: © 2015 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuron.2015.05.034
• Title of Journal or Parent Work: Neuron
• ISSN: 0896-6273
• Volume: 86
• Issue: 5
• Start Page: 1189
• End Page: 1202
• Grant/Funding Information: 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).; This study has received its main financial support from the European Union under European Research Council GA no. 281338 (to E.B.B.).; The Duke Neurogenetics Study (DNS) is supported by Duke University and the NIH (NIDA R01-DA033369).; 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.).
• Keywords: DISEASE; Neurosciences; EXPRESSION; Neurosciences & Neurology; Life Sciences & Biomedicine; GLUCOCORTICOID-RECEPTOR; Science & Technology; MAJOR DEPRESSION; ENVIRONMENT; GENOME-WIDE ASSOCIATION; SCHIZOPHRENIA; LIFE EVENTS
• Research Categories: Biology, Genetics; Biology, Neuroscience; Health Sciences, Mental Health

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 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.