Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
26050039
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.
Copyright 2015 The Authors. Published by Elsevier Inc. All rights reserved.
DATE PUBLISHED
2015 Jun 3
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2014/10/20
revised 2015/03/26
accepted 2015/05/13
entrez 2015/06/08 06:00
pubmed 2015/06/08 06:00
medline 2015/08/25 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Arloth J Arloth Janine J Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Bogdan R Bogdan Ryan R Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, USA.
Weber P Weber Peter P Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Frishman G Frishman Goar G Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.
Menke A Menke Andreas A Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Wagner KV Wagner Klaus V KV Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Balsevich G Balsevich Georgia G Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Schmidt MV Schmidt Mathias V MV Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Karbalai N Karbalai Nazanin N Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Czamara D Czamara Darina D Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Altmann A Altmann Andre A Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Palo Alto, CA 94304, USA.
Trümbach D Trümbach Dietrich D Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.
Wurst W Wurst Wolfgang W 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.
Mehta D Mehta Divya D Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Uhr M Uhr Manfred M Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Klengel T Klengel Torsten T Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Erhardt A Erhardt Angelika A Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Carey CE Carey Caitlin E CE Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, USA.
Conley ED Conley Emily Drabant ED 23andMe, Mountain View, CA 94043, USA.
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC)
Ruepp A Ruepp Andreas A Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.
Müller-Myhsok B Müller-Myhsok Bertram B Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Hariri AR Hariri Ahmad R AR Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA.
Binder EB Binder Elisabeth B EB 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.
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium PGC
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Ripke Stephan S
Wray Naomi R NR
Lewis Cathryn M CM
Hamilton Steven P SP
Weissman Myrna M MM
Breen Gerome G
Byrne Enda M EM
Blackwood Douglas H R DH
Boomsma Dorret I DI
Cichon Sven S
Heath Andrew C AC
Holsboer Florian F
Lucae Susanne S
Madden Pamela A F PA
Martin Nicholas G NG
McGuffin Peter P
Muglia Pierandrea P
Noethen Markus M MM
Penninx Brenda P BP
Pergadia Michele L ML
Potash James B JB
Rietschel Marcella M
Lin Danyu D
Müller-Myhsok Bertram B
Shi Jianxin J
Steinberg Stacy S
Grabe Hans J HJ
Lichtenstein Paul P
Magnusson Patrik P
Perlis Roy H RH
Preisig Martin M
Smoller Jordan W JW
Stefansson Kari K
Uher Rudolf R
Kutalik Zoltan Z
Tansey Katherine E KE
Teumer Alexander A
Viktorin Alexander A
Barnes Michael R MR
Bettecken Thomas T
Binder Elisabeth B EB
Breuer René R
Castro Victor M VM
Churchill Susanne E SE
Coryell William H WH
Craddock Nick N
Craig Ian W IW
Czamara Darina D
De Geus Eco J EJ
Degenhardt Franziska F
Farmer Anne E AE
Fava Maurizio M
Frank Josef J
Gainer Vivian S VS
Gallagher Patience J PJ
Gordon Scott D SD
Goryachev Sergey S
Gross Magdalena M
Guipponi Michel M
Henders Anjali K AK
Herms Stefan S
Hickie Ian B IB
Hoefels Susanne S
Hoogendijk Witte W
Hottenga Jouke Jan JJ
Iosifescu Dan V DV
Ising Marcus M
Jones Ian I
Jones Lisa L
Jung-Ying Tzeng T
Knowles James A JA
Kohane Isaac S IS
Kohli Martin A MA
Korszun Ania A
Landen Mikael M
Lawson William B WB
Lewis Glyn G
MacIntyre Donald D
Maier Wolfgang W
Mattheisen Manuel M
McGrath Patrick J PJ
McIntosh Andrew A
McLean Alan A
Middeldorp Christel M CM
Middleton Lefkos L
Montgomery Grant M GM
Murphy Shawn N SN
Nauck Matthias M
Nolen Willem A WA
Nyholt Dale R DR
O'Donovan Michael M
Oskarsson Högni H
Pedersen Nancy N
Scheftner William A WA
Schulz Andrea A
Schulze Thomas G TG
Shyn Stanley I SI
Sigurdsson Engilbert E
Slager Susan L SL
Smit Johannes H JH
Stefansson Hreinn H
Steffens Michael M
Thorgeirsson Thorgeir T
Tozzi Federica F
Treutlein Jens J
Uhr Manfred M
van den Oord Edwin J C G EJ
Van Grootheest Gerard G
Völzke Henry H
Weilburg Jeffrey B JB
Willemsen Gonneke G
Zitman Frans G FG
Neale Benjamin B
Daly Mark M
Levinson Douglas F DF
Sullivan Patrick F PF
JOURNAL
VOLUME: 86
ISSUE: 5
TITLE: Neuron
ISOABBREVIATION: Neuron
YEAR: 2015
MONTH: Jun
DAY: 3
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1097-4199
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Neuron
COUNTRY: United States
ISSNLINKING: 0896-6273
NLMUNIQUEID: 8809320
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
104036 Wellcome Trust United Kingdom
R01 DA033369 NIDA NIH HHS United States
R01-DA031579 NIDA NIH HHS United States
R01-DA033369 NIDA NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Animals
Brain physiology
Cohort Studies physiology
Forecasting physiology
Gene Regulatory Networks genetics
Genetic Variation genetics
Humans genetics
Male genetics
Mental Disorders genetics
Mice genetics
Mice, Inbred C57BL genetics
Polymorphism, Single Nucleotide genetics
Risk Factors genetics
Stress, Psychological genetics
Transcriptome genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
OTHERID SOURCE
PMC4490780 NLM