Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes
Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes
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DOI：
10.1038/sj.mp.4001875
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发表时间：
2006-10-01
影响因子：
11
通讯作者：
Bahn, S.
中科院分区：
文献类型：
--
作者：
Ryan, M. M.;Lockstone, H. E.;Bahn, S.
双相情感障碍是一种严重的精神疾病，具有很强的遗传成分，但病理生理学未知。我们使用微阵列技术确定了双相情感障碍患者和匹配的健康对照者两个大脑区域的死后组织中大约 22000 个 mRNA 转录物的表达。研究人员对来自 70 名受试者的背外侧前额皮质组织和来自 30 名受试者的单独队列的眶额皮层组织进行了研究。最终分析包括 30 名双相情感障碍受试者和 31 名对照受试者的背外侧前额叶皮质，以及 10 名双相情感障碍受试者和 11 名对照受试者的眶额皮质。通过严格的统计分析以及对混杂变量的校正和多重测试来确定疾病组和对照组之间的差异。在眶额皮质中，通过微阵列分析鉴定出 393 个差异表达的转录本，并通过定量实时 PCR 验证了代表性子集。通路分析显示，参与 G 蛋白偶联受体信号传导和刺激反应（特别是免疫反应）的基因显着上调，而与泛素循环和细胞内运输相关的基因在双相情感障碍中显示出协调下调。此外，双相情感障碍中涉及突触功能的几个基因显着下调。使用微阵列分析或定量实时 PCR 未观察到背外侧前额叶皮层基因表达的显着变化。我们的研究结果表明，眶额皮质是双相情感障碍的主要参与区域，并表明多种过程受到影响。总的来说，我们的结果表明泛素通路和突触功能的失调可能是疾病过程的核心。
Bipolar affective disorder is a severe psychiatric disorder with a strong genetic component but unknown pathophysiology. We used microarray technology to determine the expression of approximately 22 000 mRNA transcripts in post-mortem tissue from two brain regions in patients with bipolar disorder and matched healthy controls. Dorsolateral prefrontal cortex tissue from a cohort of 70 subjects and orbitofrontal cortex tissue from a separate cohort of 30 subjects was investigated. The final analysis included 30 bipolar and 31 control subjects for the dorsolateral prefrontal cortex and 10 bipolar and 11 control subjects for the orbitofrontal cortex. Differences between disease and control groups were identified using a rigorous statistical analysis with correction for confounding variables and multiple testing. In the orbitofrontal cortex, 393 differentially expressed transcripts were identified by microarray analysis and a representative subset was validated by quantitative real-time PCR. Pathway analysis revealed significant upregulation of genes involved in G-protein coupled receptor signalling and response to stimulus (in particular the immune response), while genes relating to the ubiquitin cycle and intracellular transport showed coordinated downregulation in bipolar disorder. Additionally, several genes involved in synaptic function were significantly downregulated in bipolar disorder. No significant changes in gene expression were observed in the dorsolateral prefrontal cortex using microarray analysis or quantitative real-time PCR. Our findings implicate the orbitofrontal cortex as a region prominently involved in bipolar disorder and indicate that diverse processes are affected. Overall, our results suggest that dysregulation of the ubiquitin pathway and synaptic function may be central to the disease process.