Schizophrenia interactome mapping and global discovery of brain splice variants

描述(申请人提供)：精神分裂症(SZ)是一种复杂的遗传性疾病，一生的风险约为1%。最近的技术创新为了解SZ的遗传基础打开了一扇新的窗口。基于多个小组使用不同的方法检查全基因组关联(GWA)以及拷贝数变异(CNV)和单核苷酸多态(SNPs)与SZ的关联的工作，多个危险因素已被明确识别。现在可以对它们进行实验研究，以了解它们的分子和神经生物学效应。这些风险因素包括带来高风险的个别罕见突变，以及带来适度影响的常见基因变异。在这里，我们假设多个基因的缺陷在SZ的发病机制中是重要的，这些基因在各自的功能上是不同的，但在细胞通路的背景下相互作用。为了验证这一假说，我们建议从“系统生物学”的角度研究SZ，目的是定义与疾病相关的蛋白质相互作用网络和功能模块。为了实现这一目标，我们提出了一种整合的方法来构建SZ蛋白-蛋白质相互作用网络(即SZ相互作用组)，该网络包括SZ风险基因、它们的脑剪接变体以及被SZ患者基因组缺失和复制断点干扰的基因的突变转录本。具体目标如下。(1)利用我们最近开发的结合并行454FLX测序和计算分析平台的高通量异构体发现流水线，大规模发现SZ候选基因的脑选择性剪接异构体；(2)鉴定和克隆SZ患者基因组缺失和复制断点中断的基因的突变转录本；(3)构建SZ候选基因及其选择性剪接变体和突变转录本的相互作用组，以确定与SZ病理有关的关键功能模块。这项研究的结果将对了解精神分裂症背后的细胞通路做出实质性贡献。 公共卫生相关性：这项研究的结果将对我们了解精神分裂症的原因和认知发展做出实质性贡献。连接精神分裂症候选基因及其剪接变异体和突变体的功能模块的发现是理解疾病发展机制的重要一步。该项目的最终目标是定义特定的与精神分裂症相关的蛋白质相互作用，这些蛋白质相互作用可以作为治疗的靶点。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a complex genetic disorder with a lifetime risk of approximately 1%. Recent technological innovations have opened a new window into the genetic basis of SZ. Based on work by multiple groups using different approaches to examine genome-wide association (GWA), and the association of copy number variants (CNVs) and single nucleotide polymorphisms (SNPs) with SZ, multiple risk factors have been definitively identified. They can now be studied experimentally to understand their molecular and neurobiological effects. These risk factors include individually-rare mutations that confer high risk as well as common genetic variants that confer modest effects. Here, we hypothesize that defects in multiple genes that are diverse in their individual functions, but interact within the context of cellular pathways are important for SZ pathogenesis. To test this hypothesis, we propose to investigate SZ from the "systems biology" perspective with the aim of defining protein interaction networks and functional modules that are relevant to the disease. To achieve this goal, we propose an integrative approach to build SZ protein-protein interaction network (i.e. SZ interactome) that includes SZ risk genes, their brain splice variants and mutant transcripts of the genes that are disrupted by the breakpoints of genomic deletions and duplications in SZ patients. The specific aims are as follows. (1) Perform a large-scale discovery of brain alternatively spliced isoforms of SZ gene candidates using our recently developed high-throughput isoform discovery pipeline that incorporates parallel 454 FLX sequencing and computational analysis platforms; (2) Identify and clone mutant transcripts of the genes disrupted by the breakpoints of genomic deletions and duplications in SZ patients; (3) Build an interactome of SZ candidate genes, their alternatively spliced variants and mutant transcripts to define key functional modules involved in SZ pathology. The results of this study will make substantial contributions to knowledge of the cellular pathways that underlie schizophrenia. PUBLIC HEALTH RELEVANCE: The results of this study will make substantial contributions to our knowledge of the causes of schizophrenia and of cognitive development. The discovery of functional modules that connect schizophrenia candidate genes, their splice variants and mutants is an important step towards understanding the mechanism of disease development. The final goal of this project is to define specific schizophrenia-relevant protein interactions that could be targeted therapeutically.