2/3-Identifying regulatory mutations that influence neuropsychiatric disease

2/3-识别影响神经精神疾病的调节突变

• 批准号: 9282488
• 负责人: MATTHEW W. STATE
• 金额: $ 138.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282488
• 关键词: Affect; Autistic Disorder; Brain Diseases; Cells; Childhood Schizophrenia; DNA; Data; Development; Diagnosis; Disease; Gene Expression; Gene Expression Profiling; Gene Frequency; Genes; Genetic Variation; Genome; Genomic Segment; Genomics; Goals; Knowledge; Lead; Mendelian disorder; Mutation; Neurons; Nucleic Acid Regulatory Sequences; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Population Genetics; RNA Sequences; Regulation; Resolution; Risk; Role; Sample Size; Scheme; Schizophrenia; Source; Specificity; Testing; Tissues; Untranslated RNA; Variant; Work; cell type; genome-wide; improved; induced pluripotent stem cell; interest; neuropsychiatric disorder; neuropsychiatry; new therapeutic target; patient subsets; public health relevance; transcriptome; transcriptome sequencing; whole genome

 DESCRIPTION (provided by applicant): The overarching goal of this study is the development of a framework to identify causal regulatory mutations in patients with serious neuropsychiatric presentations through the paired analyses of whole genome sequence and high resolution RNA sequence data from both accessible primary cells (PBMC and buccal cells) and reprogrammed neuronal cells from the same patients. The latter constitutes a particularly exciting opportunity as it will allow us to assay gene expression during different developmental stages of previously inaccessible cell types of much greater relevance to patient phenotype than the circulating cells DNA studies are customarily performed on. Specifically, we will interpret the effects of the regulatory variants in different developmental stages of the reprogrammed neuronal and other cells of interest with a comparison to the PBMC and buccal cells helping to interpret the specificity or generality of the relevant effects in different tissues. These analyses will focus nt only on mapping cis- and trans-acting eQTLs, but will also deploy new variant prioritization schemes that integrate knowledge of regulatory regions of the genome through ENCODE and related efforts as well as population genetic data. While an explicit aim of the work is to identif regulatory variants influencing risk of schizophrenia and autism, we emphasize that this work has primarily the broader goal of the development of appropriate frameworks for the eventual identification of such mutations, which inevitably will require substantially larger sample sizes that currently feasible to facilitate systematic discovery.

 描述（适用提供）：这项研究的总体目标是开发一个框架，通过对整个基因组序列和高分辨率RNA序列数据的配对分析，从两个可访问的原代细胞（PBMC和Bucccal细胞）和重编程神经元患者和重编程神经元患者中，通过对整个基因组序列和高分辨率RNA序列数据进行的配对分析进行了严重的神经精神病患者的灾难性调节突变。后者构成了一个特别令人兴奋的机会，因为与循环细胞DNA研究相比，与患者表型相关的先前无法接近的细胞类型的不同发育阶段的不同发育阶段中，我们可以主张基因表达。具体而言，我们将在重编程的神经元和其他感兴趣的细胞的不同发育阶段解释调节变体的影响，与PBMC和颊细胞进行比较，有助于解释不同组织中相关效应的特异性或一般性。这些分析将仅着重于绘制顺式和跨作用EQTL，但还将部署新的变体优先计算方案，这些方案通过编码和相关工作以及人群遗传数据来整合基因组调节区域的知识。尽管这项工作的明确目的是确定监管变体会影响精神分裂症和自闭症的风险，但我们强调，这项工作的主要目标是开发适当的框架以最终确定此类突变的目标，而这种突变最终将不可避免地需要实质上更大的样本量，而这些样本量当前可行，以促进系统发现。