1/3-Identifying regulatory mutations that influence neuropsychiatric disease

1/3-识别影响神经精神疾病的调节突变

• 批准号: 8805881
• 负责人: David B. Goldstein
• 金额: $ 12.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805881
• 关键词: Affect; Autistic Disorder; Biological Assay; Brain Diseases; Cells; Childhood Schizophrenia; DNA; Data; Development; Diagnosis; Disease; Functional RNA; Gene Expression; Gene Expression Profile; Gene Frequency; Genes; Genetic Variation; Genome; Genomics; Goals; Knowledge; Lead; Maps; 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; Staging; Testing; Tissues; Variant; Work; cell type; genome sequencing; genome-wide; improved; induced pluripotent stem cell; interest; neuropsychiatry; new therapeutic target; public health relevance

 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（通过应用程序证明）：开发一个框架的总体目标，以识别具有严重神经精神病存在的ENTS的整个基因组和高分辨率RNA序列数据的配对分析，可访问的原代细胞（PBMC和Buccal细胞）和重编程的神经元细胞从同一位患者中，在以前无法访问的细胞中，与循环细胞研究相比，我们将在先前无法访问的细胞中进行大量绿色的细胞类型的发育阶段。与PBMC和颊细胞进行比较的神经元细胞有助于在不同组织中相关效应的特异性或一般性。努力和人口遗传数据。 。