1/3-Identifying regulatory mutations that influence neuropsychiatric disease

 描述（由申请方提供）：本研究的总体目标是开发一个框架，通过对来自同一患者的可接近原代细胞（PBMC和颊细胞）和重编程神经元细胞的全基因组序列和高分辨率RNA序列数据进行配对分析，鉴定严重神经精神症状患者的因果调节突变。后者构成了一个特别令人兴奋的机会，因为它将使我们能够在以前无法接近的细胞类型的不同发育阶段期间测定基因表达，这些细胞类型与患者表型的相关性比通常进行的循环细胞DNA研究大得多。我们将解释调节变体在重编程神经元和其他感兴趣的细胞的不同发育阶段中的作用，PBMC和颊细胞的特异性或一般性，有助于解释不同组织中相关效应的特异性或一般性。这些分析将不仅集中于顺式和反式作用eQTL的定位，而且还将部署新的变体优先级排序方案，该方案通过ENCODE和相关工作以及群体遗传数据整合基因组调控区域的知识。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主要是为了最终确定此类突变而开发适当框架的更广泛目标，这不可避免地需要目前可行的更大样本量以促进系统发现。

 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.