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

Arloth J 1 , Bogdan R 2 , Weber P 1 , Frishman G 3 , Menke A 1 , Wagner KV 4 Show all authors , Balsevich G 4 , Schmidt MV 4 , Karbalai N 1 , Czamara D 1 , Altmann A 5 , Trümbach D 3 , Wurst W 6 , Mehta D 1 , Uhr M 1 , Klengel T 1 , Erhardt A 1 , Carey CE 2 , Conley ED 7 , Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC) , Ruepp A 3 , Müller-Myhsok B 1 , Hariri AR 8 , Binder EB 9 , Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium PGC

Affiliations 

  • 1 Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany
  • 2 Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, USA
  • 3 Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany
  • 4 Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany
  • 5 Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Palo Alto, CA 94304, USA
  • 6 Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany; Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany; Technische Universität München, c/o Helmholtz Zentrum München, German Research Centre for Environmental Health, Institute of Developmental Genetics, Neuherberg 85764, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Site Munich, Munich 80336, Germany
  • 7 23andMe, Mountain View, CA 94043, USA
  • 8 Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA
  • 9 Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30329, USA. Electronic address: binder@psych.mpg.de
Neuron, 2015 Jun 03;86(5):1189-202.
PMID: 26050039 DOI: 10.1016/j.neuron.2015.05.034

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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