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: 9316735
• 负责人: David B. Goldstein
• 金额: $ 137.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316735
• 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（由申请人提供）：本研究的总体目标是开发一个框架，通过对全基因组序列和来自两个可访问的原代细胞的高分辨率 RNA 序列数据进行配对分析，识别患有严重神经精神疾病的患者的因果调节突变。 PBMC 和颊细胞）和来自同一患者的重编程神经元细胞构成了一个特别令人兴奋的机会，因为它将使我们能够分析以前无法访问的细胞类型在不同发育阶段的基因表达，这些细胞类型与患者表型的相关性比这要大得多。具体来说，我们将通过与 PBMC 和颊细胞的比较来解释重编程神经细胞和其他感兴趣细胞的不同发育阶段的调节变异的影响，以帮助解释特异性或普遍性。这些分析将仅侧重于绘制顺式和反式作用 eQTL，但还将部署新的变异优先级方案，通过 ENCODE 和相关工作整合基因组调控区域的知识，例如虽然这项工作的明确目标是确定影响精神分裂症和自闭症风险的调节变异，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识别此类突变，这不可避免地需要更大的样本量，以促进系统发现目前可行。