Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.
Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.
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DOI：
10.1016/j.neuron.2015.05.034
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发表时间：
2015-06-03
期刊：
影响因子：
16.2
通讯作者：
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium PGC
中科院分区：
文献类型：
--
作者：
Arloth J;Bogdan R;Weber P;Frishman G;Menke A;Wagner KV;Balsevich G;Schmidt MV;Karbalai N;Czamara D;Altmann A;Trümbach D;Wurst W;Mehta D;Uhr M;Klengel T;Erhardt A;Carey CE;Conley ED;Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC);Ruepp A;Müller-Myhsok B;Hariri AR;Binder EB;Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium PGC
遗传因素和压力暴露加剧了抑郁症的风险;然而，这些因素相互作用以产生抑郁症风险的生物学机制却知之甚少。一种假定的生物学机制涉及响应于压力而释放的皮质醇的能力的可变性，其通过糖皮质激素受体（GR）激活来触发适应性基因组和非基因组过程的级联。在这里，我们证明了常见的遗传变异的远程增强子元件调节即时转录反应GR激活人血细胞。这些功能性遗传变异增加了患抑郁症和共同遗传性精神疾病的风险。此外，这些风险变异与不适当的杏仁核反应，一个transdiagnosis精神病内表型和一个重要的应激激素反应触发。网络建模和动物实验表明，GR诱导的转录激活中的这些遗传差异可能通过改变血液和大脑中功能相关的压力敏感基因网络来介导抑郁症和其他精神疾病的风险。这些功能性SNP可预测精神疾病的风险，但不能预测其他医学疾病的风险。这些变体与对威胁的不同神经回路反应相关。GR转录物在动物模型的脑中强烈共表达和调节。表明改变对应激激素受体激活初始转录组反应的常见遗传变异也累积地增加了与应激相关的精神疾病的风险，并预测了来自杏仁核的威胁反应。
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. SNPs in long-range enhancers alter the transcriptional response of GR target genes These functional SNPs predict risk for psychiatric but not other medical disorders These variants are associated with differential neural circuit responses to threat GR transcripts are strongly co-expressed and regulated in the brain of animal models Using a stimulated eQTL approach, Arloth et al. show that common genetic variants that alter the initial transcriptome response to stress hormone receptor activation also cumulatively increase the risk for stress-related psychiatric disorders and predict a threat response from the amygdala.
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