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.

我们的团队已经做好了为GTEx做出实质性贡献的准备， 实验和统计方法的表观遗传学现在普遍使用。我们发现了CpG岛海岸， 比CpG岛本身更大的疾病和人口变异的区域，以及大的 低甲基化块。我们还率先努力鉴定组织特异性差异甲基化的 区域或t-DMR和群体可变甲基化区域或VMR。最后，我们一直是 整合甲基化、SNP和表达数据以定义疾病相关表型。特别 由于这一应用的重要性，我们已带头努力在人口一级应用这些方法。在这 应用程序，我们采取的战略方法主要集中在心理健康相关的大脑区域，但也 组织变异的普遍问题。我们关注心理健康是因为所有人类疾病都是 由于临床检查固有的主观性，仍然特别难以理解;以及 我们最近开发的用于将神经元和胶质细胞特异性信号去卷积为总信号的方法的价值 DNA甲基化和差异甲基化，对大脑非常重要，但通常对GTEx也很重要。 在目标1中，我们将使用全基因组亚硫酸氢盐测序（WGBS）来鉴定脑区域特异性VMR， 以及四个地区的t-DMR，这些地区对三种毁灭性的精神疾病特别重要， 精神分裂症、抑郁症和成瘾：即前扣带皮层、额叶皮层、海马体和 丘脑核我们将研究足够数量的样本（来自匹配患者的各30份样本），以确定 t-DMR和VMR。VMR的识别需要更大的样本数量，因为根据定义， 在不同的人的大脑区域中是不同的。我们已经表明，t-DMR是相对较差的指标， VMR，但VMR更可能与种群中的遗传变异有关。我们将 用相同脑区的羟甲基胞嘧啶测序补充该分析，因为 这种改变在大脑中的潜在重要性。我们还将纳入5个额外的GTEx组织， 与资源中的许多其他资源相比，具有合理的同质性。这些将作为对照，例如 为了比较大脑区域之间的变异性与跨组织的变异性，并且还为了另外的目的， t-DMR识别。在目标2中，我们将进行捕获亚硫酸氢盐测序以识别大脑区域特异性 群体中的VMR，研究大量个体（100），以将差异甲基化 基因型和基因表达，并靶向目标1中鉴定的VMR和t-DMR。我们还将 初步分析VMRs与遗传变异和基因表达的关系， 现有的GTEx表达和遗传变异数据。这里提出的工作将提供一个关键的 为研究精神疾病的研究人员提供了一个强大的平台和数据集， 基因表达、甲基化和DNA序列之间的关系。