Consistently altered expression of gene sets in postmortem brains of individuals with major psychiatric disorders.
Consistently altered expression of gene sets in postmortem brains of individuals with major psychiatric disorders.
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DOI：
10.1038/tp.2016.173
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发表时间：
2016-09-13
影响因子：
6.8
通讯作者：
Sabunciyan S
中科院分区：
文献类型：
--
作者：
Darby MM;Yolken RH;Sabunciyan S
死后脑组织基因表达的测定是了解严重精神疾病发病机制的重要工具。我们假设与精神疾病相关的主要分子缺陷会影响整个大脑，并且这种缺陷可能在各种疾病中共享。我们进行了RNA测序和定量基因表达的100个大脑的海马在斯坦利阵列收集，然后复制在57个大脑的眶额皮质在斯坦利神经病理学协会。然后，我们确定了基因和经典途径基因集与显着改变的表达在精神分裂症和双相情感障碍的海马和精神分裂症，双相情感障碍和抑郁症的眶额皮质。虽然单个基因的表达各不相同，但基因组在两个大脑区域都显着富集，其中许多在诊断组中是一致的。对在两个脑区和跨靶疾病中表达一致增加或减少的核心基因集的进一步检查显示，与没有精神疾病的对照相比，在受影响的个体中，核糖体基因过表达，而参与神经元过程、GABA能信号传导、内吞作用和抗原加工的基因的表达主要减少。我们的研究结果突出了对精神健康至关重要的途径，并强调信使RNA加工和蛋白质合成是所有三种疾病的潜在治疗靶点。
The measurement of gene expression in postmortem brain is an important tool for understanding the pathogenesis of serious psychiatric disorders. We hypothesized that major molecular deficits associated with psychiatric disease would affect the entire brain, and such deficits may be shared across disorders. We performed RNA sequencing and quantified gene expression in the hippocampus of 100 brains in the Stanley Array Collection followed by replication in the orbitofrontal cortex of 57 brains in the Stanley Neuropathology Consortium. We then identified genes and canonical pathway gene sets with significantly altered expression in schizophrenia and bipolar disorder in the hippocampus and in schizophrenia, bipolar disorder and major depression in the orbitofrontal cortex. Although expression of individual genes varied, gene sets were significantly enriched in both of the brain regions, and many of these were consistent across diagnostic groups. Further examination of core gene sets with consistently increased or decreased expression in both of the brain regions and across target disorders revealed that ribosomal genes are overexpressed while genes involved in neuronal processes, GABAergic signaling, endocytosis and antigen processing have predominantly decreased expression in affected individuals compared to controls without a psychiatric disorder. Our results highlight pathways of central importance to psychiatric health and emphasize messenger RNA processing and protein synthesis as potential therapeutic targets for all three of the disorders.
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