Strategic mapping of tissue and population methylation for mental health research

用于心理健康研究的组织和群体甲基化的战略图谱

• 批准号: 8642752
• 负责人: ANDREW P. FEINBERG
• 金额: $ 101.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8642752
• 关键词: Anterior; Biological Assay; Brain; Brain region; Calibration; Clinical; Communities; Complement; CpG Islands; DNA Methylation; DNA Sequence; Data; Data Set; Development; Disease; Epigenetic Process; Foundations; Gene Expression; Genes; Genetic Variation; Genome; Genotype; Health; Heart; Hippocampus (Brain); Individual; Island; Kidney; Liver; Location; Maps; Mental Depression; Mental Health; Mental disorders; Methods; Methylation; Modification; Neuroglia; Neurons; Nucleus Accumbens; Patients; Phenotype; Play; Population; Population Study; Quality Control; RNA Sequences; Regulator Genes; Research; Research Personnel; Resources; Role; Sampling; Schizophrenia; Signal Transduction; Skeletal Muscle; Sorting - Cell Movement; Statistical Methods; Thyroid Gland; Tissues; Variant; Work; addiction; bisulfite; cingulate cortex; cost; design; frontal lobe; genome analysis; human disease; methylome; novel; public health relevance

Our group is extremely well poised to make a substantial contribution to GTEx, having developed many of experimental and statistical methods for epigenetics now in general use. We discovered CpG island shores, regions of greater disease and population variation than the CpG islands themselves, as well as large hypomethylated blocks. We also pioneered efforts to identify both tissue-specific differentially methylated regions, or t-DMRs, and population variable methylated regions, or VMRs. Finally, we have been pioneers in the integration of methylation, SNP, and expression data to define disease-relevant phenotypes. Of particular importance to this application, we have led efforts to apply these methods on a population level. In this application, we take a strategic approach primarily focused on mental health relevant brain regions, but also on the general question of tissue variation. Our focus on mental health is because of all human diseases these remain particularly opaque to understanding due to the inherent subjectivity of clinical examination; as well as the value of our recently developed methods for deconvoluting the neuron- and glia-specific signals to total DNA methylation and to differential methylation, of great importance for the brain but also to GTEx generally. In Aim 1, we will use whole genome bisulfite sequencing (WGBS) to identify brain region-specific VMRs as well as t-DMRs in four regions of particular importance to three devastating mental health disorders, schizophrenia, depression, and addiction: namely anterior cingulate cortex, frontal cortex, hippocampus, and nucleus accumbens. We will study a sufficient number of samples (30 each from matched patients) to identify both t-DMRs and VMRs. Identification of VMRs requires this larger sample number, since by definition they are variable within a brain region, across individuals. We have shown that t-DMRs are relatively poor indicators of VMRs, but it is the VMRs that are more likely to be related to genetic variation in the population. We will complement this analysis with hydroxymethylcytosine sequencing of the same brain regions because of the potential importance of this modification in the brain. We will also include 5 additional GTEx tissues that exist in reasonable homogeneity compared to many others in the resource. These will serve as controls, for example to compare variability between brain regions to variability across tissues, and also for the purpose of additional t-DMR identification. In Aim 2, we will perform capture bisulfite sequencing to identify brain region-specific VMRs in the population, studying a larger number of individuals (100), in order to relate differential methylation to genotype and gene expression, and targeting the VMRs and t-DMRs identified in Aim 1. We will also perform preliminary analysis of the relationship of VMRs and genetic variation and gene expression, using the existing GTEx data on expression and genetic variation. The work proposed here will provide a critical resource for investigators studying psychiatric disease, and will provide a robust platform and datasets for relating gene expression, methylation, and DNA sequence across populations.

我们的小组非常准备为GTEX做出重大贡献，并发展了许多 现在一般使用表观遗传学的实验和统计方法。我们发现了CPG岛海岸， 比CpG岛本身，疾病和人口变化更大的地区以及大型地区 低甲基化块。我们还开创了识别两个组织特异性差甲基化的努力 区域或T-DMR和人口可变的甲基化区域或VMR。最后，我们一直是先驱 甲基化，SNP和表达数据的整合以定义与疾病相关的表型。特别 对于此应用程序，我们领导了将这些方法应用于人群级别的努力。在这个 应用，我们采用一种战略方法，主要关注与心理健康相关的大脑区域，但也关注 组织变异的一般问题。我们对心理健康的关注是因为所有人类疾病 由于临床检查的固有主观性，理解仍然特别不透明；也 我们最近开发的方法是将神经元和神经胶质特异性信号变成总计的方法 DNA甲基化和差异甲基化，对大脑以及对GTEX的重要性非常重要。 在AIM 1中，我们将使用整个基因组Bisulfite测序（WGB）来识别大脑区域特异性VMR作为 以及对于三个毁灭性心理健康障碍特别重要的四个地区的T-DMR， 精神分裂症，抑郁和成瘾：前扣带回皮质，额叶皮层，海马和 伏隔核。我们将研究足够数量的样本（每个匹配患者的30个）来识别 T-DMR和VMR。 VMR的识别需要此较大的样本号，因为根据定义，它们是 大脑区域内的变量，跨个体。我们已经表明，T-DMR是相对较差的指标 VMR，但VMR更可能与人群的遗传变异有关。我们将 通过相同大脑区域的羟基胞嘧啶测序补充这种分析，因为 这种修饰在大脑中的潜在重要性。我们还将包括5种其他存在的GTEX组织 与资源中的许多其他人相比，合理的同质性。例如，这些将作为控件 比较大脑区域之间的变异性与组织之间的变异性，也是为了额外的目的 T-DMR识别。在AIM 2中，我们将执行捕获的甲硫酸盐测序以识别特异性大脑区域特异性 人口中的VMR，研究了更多个体（100），以关联差分甲基化 对基因型和基因表达，靶向AIM 1中鉴定的VMR和T-DMR。我们还将 对VMR与遗传变异和基因表达的关系进行初步分析，使用 现有的有关表达和遗传变异的GTEX数据。这里提出的工作将提供关键 研究精神病疾病的研究人员的资源，并将提供一个强大的平台和数据集 跨种群中的基因表达，甲基化和DNA序列。