1/3-Identifying regulatory mutations that influence neuropsychiatric disease

 描述(申请人提供)：这项研究的首要目标是开发一个框架，通过配对分析来自同一患者的可获得的原代细胞(PBMC和口腔细胞)和重新编程的神经细胞的全基因组序列和高分辨率RNA序列数据，来确定严重神经精神疾病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分析以前无法获得的细胞类型的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通常对循环细胞进行的DNA研究要大得多。具体地说，我们将解释调控变体在重新编程的神经元和其他感兴趣的细胞的不同发育阶段的影响，并与PBMC和口腔细胞进行比较，以帮助解释相关影响在不同组织中的特异性或一般性。这些分析将只侧重于绘制顺式和反式eQTL，但也将部署新的变异优先方案，通过ENCODE和相关努力整合基因组调控区域的知识以及种群遗传数据。虽然这项工作的明确目标是识别影响精神分裂症和自闭症风险的调控变异，但我们强调，这项工作主要有更广泛的目标，即为最终识别此类突变开发适当的框架，这不可避免地需要更大的样本量，目前可行，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.