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

被引：99

作者：

Arloth, Janine ^{[1
]}

Bogdan, Ryan ^{[3
]}

Weber, Peter ^{[1
]}

Frishman, Goar ^{[4
]}

Menke, Andreas ^{[1
]}

Wagner, Klaus V. ^{[10
]}

Balsevich, Georgia ^{[10
]}

Schmidt, Mathias V. ^{[10
]}

Karbalai, Nazanin ^{[1
]}

Czamara, Darina ^{[1
]}

Altmann, Andre ^{[9
]}

Truembach, Dietrich ^{[4
]}

Wurst, Wolfgang ^{[1
,4
,6
,7
]}

Mehta, Divya ^{[1
]}

Uhr, Manfred ^{[1
]}

Klengel, Torsten ^{[1
]}

Erhardt, Angelika ^{[1
]}

Carey, Caitlin E. ^{[3
]}

Conley, Emily Drabant ^{[5
]}

Ruepp, Andreas ^{[4
]}

Mueller-Myhsok, Bertram ^{[1
]}

Hariri, Ahmad R. ^{[2
]}

Binder, Elisabeth B. ^{[1
,8
]}

机构：

[1] Max Planck Inst Psychiat, Dept Translat Res Psychiat, D-80804 Munich, Germany

[2] Duke Univ, Inst Genome Sci & Policy, Dept Psychol & Neurosci, Durham, NC 27708 USA

[3] Washington Univ, Dept Psychol, St Louis, MO 63130 USA

[4] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany

[5] 23andMe, Mountain View, CA 94043 USA

[6] Tech Univ Munich, Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Dev Genet, D-85764 Neuherberg, Germany

[7] Deutsch Zentrum Neurodegenerat Erkrankung eV DZNE, D-80336 Munich, Germany

[8] Emory Univ, Dept Psychiat & Behav Sci, Sch Med, Atlanta, GA 30329 USA

[9] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA

[10] Max Planck Inst Psychiat, Dept Stress Neurobiol & Neurogenet, D-80804 Munich, Germany

来源：

NEURON | 2015年 / 86卷 / 05期

基金：

欧洲研究理事会;

关键词：

LIFE EVENTS; EXPRESSION;

D O I：

10.1016/j.neuron.2015.05.034

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

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

引用

页码：1189 / 1202

页数：14

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