Molecular Epigenetic Studies of Major Depression

重度抑郁症的分子表观遗传学研究

• 批准号: 6928813
• 负责人: Art Petronis
• 金额: $ 26.73万
• 依托单位: CENTRE FOR ADDICTION AND MENTAL HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-13 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928813
• 关键词: CpG islands; DNA methylation; behavioral genetics; bioinformatics; clinical research; disease /disorder etiology; gene environment interaction; gene expression profiling; genetic susceptibility; human data; human genetic material tag; major depression; microarray technology; molecular genetics; molecular pathology; twin /multiplet

DESCRIPTION (provided by applicant): This application is dedicated to understanding of primary molecular cause(s) of major depressive disorder (MDD). Unlike the majority of etiological studies that concentrate on genetic and/or environmental factors, the emphasis of this project is shifted to the inter-individual variation of epigenetic modifications of DMA. The epigenetic theory can provide a cohesive interpretation for numerous epidemiological, clinical, and molecular findings in MDD. Such include the non-Mendelian mode of inheritance of MDD, molecular effects of adverse life events, discordance of monozygotic twins, sex differences in susceptibility to the disease, major fluctuations in the disease course, and inconsistent findings of molecular genetic studies. In this project, two null hypotheses will be tested: i) there is no association between epigenetic changes and MDD, and ii) if such association exists, it is non-causal. Epigenetic profiles will be investigated in 850 DNA samples from: a) monozygotic twins discordant for MDD, b) unrelated MDD patients and matched controls (peripheral blood samples, post-mortem brain tissues, and sperm samples), and c) MD0D patients during remission vs. relapse. DNA methylation profiles will be identified through the microarray-based mapping of unmethylated and hypermethylated fractions of genomic DNA. Two types of microarrays will be used: i) 12,192- element CpG island microarray that interrogates gene promoter regions, and ii) 2,000-element microarray that investigates the genes of proteins that are of primary interest in MDD, such as serotonin transporter and glucocorticoid receptor. Bioinformatics tools will be used to process over 12 M microarray data points in order to identify disease specific DNA methylation changes in the affected individuals vs. controls in both within and between all the listed comparisons. If the null hypotheses cannot be rejected, the study will provide a new perspective on the fundamental issues in MDD and other complex diseases.

描述（由申请人提供）：此应用程序致力于理解主要抑郁症（MDD）的主要分子原因。与集中于遗传和/或环境因素的大多数病因研究不同，该项目的重点转移到了DMA表观遗传修饰的个体间变化。表观遗传学理论可以为MDD中的许多流行病学，临床和分子发现提供凝聚力的解释。这样的包括非孟德尔遗传模式，不良生命事件的分子效应，单卵双胞胎的不一致，对疾病的易感性的性别差异，疾病过程中的主要波动以及分子遗传学研究的不一致发现。在该项目中，将测试两个无效的假设：i）表观遗传变化与MDD之间没有关联，ii）如果存在这种关联，则是非因果的。将在850个DNA样品中研究表观遗传谱，a）MDD的单卵双胞胎不一致，b）无关的MDD患者和匹配的对照组（周围血液样本，验尸后脑组织和精子样本和精子样本），以及C）在缓解过程中的c）MD0D患者。 DNA甲基化谱将通过基于微阵列的基因组和高甲基化馏分的基于微阵列的映射来鉴定。将使用两种类型的微阵列：i）12,192-元素CpG岛微阵列询问基因启动子区域，ii）2,000个元素微阵列研究了MDD中主要兴趣的蛋白质基因，例如血清素转运蛋白转运蛋白转运蛋白和糖皮质激素受体。生物信息学工具将用于处理超过12 m的微阵列数据点，以识别受影响个体的特定DNA甲基化变化与所有列出的比较之间以及在所有列出的比较之间。如果未拒绝零假设，则该研究将为MDD和其他复杂疾病的基本问题提供新的观点。