title: Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.
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.
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Arloth
authors.affiliation: Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bogdan
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors.forename: Goar
authors.initials: G
authors.lastname: Frishman
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Menke
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Wagner
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Georgia
authors.initials: G
authors.lastname: Balsevich
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Mathias V
authors.initials: MV
authors.lastname: Schmidt
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Nazanin
authors.initials: N
authors.lastname: Karbalai
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.affiliation: Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Altmann
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors.forename: Dietrich
authors.initials: D
authors.lastname: Trümbach
authors.affiliation: 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.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Divya
authors.initials: D
authors.lastname: Mehta
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Klengel
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Erhardt
authors.affiliation: Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, USA.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Carey
authors.affiliation: 23andMe, Mountain View, CA 94043, USA.
authors.forename: Emily Drabant
authors.initials: ED
authors.lastname: Conley
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ruepp
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA.
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Hariri
authors.affiliation: 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.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D015331:Cohort Studies; D005544:Forecasting; D053263:Gene Regulatory Networks / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000175:diagnosis* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D013315:Stress, Psychological / Q000175:diagnosis / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*