Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia
Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia
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DOI：
10.1101/gr.101956.109
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发表时间：
2010-04-01
期刊：
影响因子：
7
通讯作者：
Thomas, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Torkamani, Ali;Dean, Brian;Thomas, Elizabeth A.
我们对两个基于微阵列的大型大脑基因表达数据集进行了整合基因共表达网络分析，这些数据集是从 101 名受试者（47 名精神分裂症受试者和 54 名正常对照受试者）死后获得的前额叶皮层生成的，年龄从 19 岁到 81 岁不等。在正常受试者和精神分裂症患者中均检测到了 28 个具有功能解释的共表达基因模块。观察到“病例”和“对照”模块组成的显着重叠，表明潜在分子连接性的广泛差异不太可能驱动精神分裂症的病理学。根据疾病关联、细胞类型特异性和衰老的影响来表征共表达基因的模块。我们发现精神分裂症中表达改变的基因聚集成不同的共表达网络，并且这些主要与神经元相关。我们进一步确定了年龄对区分正常受试者和精神分裂症患者的基因表达模块的强大影响。特别是，我们报告说，与中枢神经系统发育过程相关的基因（包括神经突生长、神经元分化和多巴胺相关细胞信号传导）与年龄相关的正常减少在精神分裂症患者的衰老过程中不会发生。将这些发现推断到发育的早期阶段支持了这样的概念：精神分裂症的发病机制开始于生命早期，并且与发育相关基因表达的正常下降失败有关。这些发现为分子水平上的精神分裂症“发育”假说提供了一种新的机制。
We performed integrated gene coexpression network analysis on two large microarray-based brain gene expression data sets generated from the prefrontal cortex obtained post-mortem from 101 subjects, 47 subjects with schizophrenia and 54 normal control subjects, ranging in age from 19 to 81 years. Twenty-eight modules of coexpressed genes with functional interpretations were detected in both normal subjects and those with schizophrenia. Significant overlap of "case'' and "control'' module composition was observed, indicating that extensive differences in underlying molecular connectivity are not likely driving pathology in schizophrenia. Modules of coexpressed genes were characterized according to disease association, cell type specificity, and the effects of aging. We find that genes with altered expression in schizophrenia clustered into distinct coexpression networks and that these were associated primarily with neurons. We further identified a robust effect of age on gene expression modules that differentiates normal subjects from those with schizophrenia. In particular, we report that normal age-related decreases in genes related to central nervous system developmental processes, including neurite outgrowth, neuronal differentiation, and dopamine-related cellular signaling, do not occur in subjects with schizophrenia during the aging process. Extrapolating these findings to earlier stages of development supports the concept that schizophrenia pathogenesis begins early in life and is associated with a failure of normal decreases in developmental-related gene expression. These findings provide a novel mechanism for the "developmental'' hypothesis of schizophrenia on a molecular level.