DNA METHYLOME ANALYSIS IN BIPOLAR DISORDER

双相情感障碍的 DNA 甲基化分析

• 批准号: 8298887
• 负责人: Art Petronis
• 金额: $ 78.32万
• 依托单位: CENTRE FOR ADDICTION AND MENTAL HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298887
• 关键词: Address; Affect; Agreement; Bioinformatics; Bipolar Disorder; Brain; Chemicals; Collaborations; Communities; CpG Islands; DNA; DNA Methylation; Data; Data Analyses; Dependence; Diagnostic; Disease; Disease Marker; Environmental Risk Factor; Epigenetic Process; Epithelial Cells; Gene Expression Regulation; Genes; Genome; Guidelines; Heterogeneity; Human; Individual; Inherited; Lead; Leukocytes; Literature; Measurement; Mental disorders; Microarray Analysis; Minor; Molecular; Monozygotic twins; Nature; Neuroglia; Neurons; Patients; Pharmaceutical Preparations; Prefrontal Cortex; Process; Prophylactic treatment; Proteins; Psychotic Disorders; Regulation; Research; Risk; Role; Sampling; Scanning; Schizophrenia; Testing; Tissues; base; brain tissue; computerized data processing; density; design; epigenomics; interest; next generation; peripheral blood; research study; sex; tool

DESCRIPTION (provided by applicant): Epigenetic misregulation is consistent with various non-Mendelian features of bipolar disorder (BPD), such as the discordance of identical twins, significant fluctuations in disease course, sex- and parental origin- effects, and the presence of familial and sporadic cases. To date, however, few studies have investigated the role of epigenetic factors in BPD and other psychiatric disease, and none have utilized an epigenome-wide approach. In our recent study, we used 12,192- feature containing CpG-island microarrays to identify DNA methylation changes in the prefrontal cortex of individuals affected with BPD and schizophrenia. In this study, we found evidence for psychosis-associated DNA methylation differences in several dozen loci. While this effort proved the principle that microarray-based DNA methylation profiling can reveal epigenetic changes in psychiatric patients, the first epigenome scan tested a small sample, explored only ~0.5% of the epigenome, and likely revealed only minor epigenetic changes, most of which are non-causal for major psychosis. This project is dedicated to a second, much more powerful and comprehensive epigenomic analysis of BPD. The main objective of this project is to identify major etiological epimutations in BPD. We will scan the entire non-repetitive genome in 1,000 DNA samples from BPD patients and controls using high density Affymetrix tiling microarrays. In comparison to the previous study, we have increased the sample of post-mortem brain tissues 3-fold (100 BPD patients and 100 controls). We will investigate DNA methylomes in neurons separately from the glial cells, which will help to estimate the confounding effects of cellular heterogeneity in the brain. In addition to the brain sample, a full microarray- based DNA methylation scan will be performed on peripheral blood leukocytes, buccal epithelial cells, and germline of BPD patients and controls. This effort should help i) to address cause-effect relationship between the detected epigenetic changes and BPD, ii) to identify heritable BPD epimutations, and iii) to uncover the networks of inter- dependence of epigenetic regulation of human genes across different tissues of BPD patients and control individuals. The project will generate ~10 billion microarray data points that will be processed using a battery of bioinformatics tools. The raw and processed data will be shared with the scientific community via our collaboration with the Epigenomics Data Analysis and Coordination Center (EDACC). The project should help us understand the molecular basis for the inherited and acquired nature of BPD, and further define the methodological guidelines for epigenomic studies in psychiatric research. The identification of epigenetic disease markers would be of critical importance in the diagnostic, treatment, and prophylactic applications in BPD. They may also bring new opportunities for the rational design of the next generation of drugs for BPD.

描述（由申请人提供）：表观遗传上的错误调节与躁郁症（BPD）的各种非孟德尔特征一致，例如相同的双胞胎的不一致，疾病过程中的显着波动，性和父母起源，以及家族性和零星病例的存在。然而，迄今为止，很少有研究研究表观遗传因素在BPD和其他精神病疾病中的作用，并且没有一种使用表观遗传学的方法。在我们最近的研究中，我们使用了12,192个特征，其中包含CPG-ISLAND微阵列来鉴定受BPD和精神分裂症影响的个体前额叶皮层的DNA甲基化变化。在这项研究中，我们发现了几十个基因座中与精神病相关的DNA甲基化差异的证据。尽管这项工作证明了基于微阵列的DNA甲基化分析可以揭示精神病患者的表观遗传变化的原则，但第一个表观遗传组扫描测试了一个小样本，仅探索了〜0.5％的表观基因组，并且可能仅显示出轻微的表观遗传学变化，其中大多数是非疾病的主要精神病。该项目致力于对BPD进行的第二个更强大，更全面的表观基因组分析。该项目的主要目的是识别BPD中的主要病因学表现。我们将使用高密度Affymetrix瓷砖微阵列中的1,000例BPD患者的DNA样品中扫描整个非重复基因组。与先前的研究相比，我们增加了3倍（100 BPD患者和100个对照）的验尸后脑组织样本。我们将与神经胶质细胞分开研究神经元中的DNA甲基团，这将有助于估计大脑细胞异质性的混杂作用。除了大脑样品外，还将对BPD患者和对照组的外周血白细胞，颊上皮细胞和生殖线进行完整的基于微阵列的DNA甲基化扫描。这项工作应有助于i）解决检测到的表观遗传变化与BPD之间的原因效应关系，ii）鉴定可遗传的BPD表演，iii）揭示了跨BPD患者和对照组的不同组织中人类基因表观遗传调节的依赖性网络。该项目将产生约100亿个微阵列数据点，这些数据点将使用一系列的生物信息学工具来处理。原始数据和处理的数据将通过我们与表观基因组学数据分析与协调中心（EDACC）的合作与科学界共享。该项目应有助于我们了解BPD的遗传和获得性质的分子基础，并进一步定义精神研究中表观基因组研究的方法论指南。在BPD中的诊断，治疗和预防性应用中，表观遗传疾病标志物的鉴定至关重要。他们还可能为BPD的下一代药物的合理设计带来新的机会。