Design and Analysis of Multi-Staged Association Studies Using Pooled Genomic DNA

描述（由申请人提供）：在一次测定中同时对数十万个单核苷酸多态性（SNP）进行基因分型的技术最近才开发出来，并有可能彻底改变我们在复杂疾病中识别疾病相关基因的能力。具体而言，高密度SNP基因分型为病例对照全基因组关联研究打开了可能性，从而可以发现与复杂的多基因疾病进化相关的SNP，以及与功能突变密切相关的SNP。全基因组关联研究的主要缺点是，它们需要数百到数千个病例和匹配良好的对照才能提供足够的动力。这种类型的研究预计将花费数百万美元使用个人基因分型。本提案的总体目标是开发具有成本效益的设计策略和相应的分析工具，用于使用合并的基因组DNA进行全基因组病例对照SNP关联研究。 我们将开发新的分析工具和设计策略，利用我们无与伦比的高密度全基因组SNP基因分型数据进行全基因组关联研究。在过去的六个月里，我们对5,000多个样本进行了全基因组微阵列SNP扫描。目前，我们是Affytelum 500 K Mapping阵列的抢先体验站点，并已使用该平台完成了对合并DNA的两次全基因组扫描，验证了先前已知的进行性核上性麻痹（PSP）的疾病位点，并确定了几个新的位点。我们将获得来自多个全基因组关联研究的数据集，这些研究涉及合并的基因组DNA，包括高血压、阿尔茨海默病（AD）、自闭症、双相情感障碍、黑色素瘤、PSP、记忆和糖尿病。对于AD，我们将在1,000例病例和1,000例对照中获得500 K + SNP的合并和个体基因型。此外，我们在本提案中纳入了对指导社区决定的样本和疾病的合并基因组DNA进行全基因组关联研究的资金。在这项研究的过程中，我们将提供基于网络的内容和软件工具：（1）帮助全基因组关联研究的总体设计，其中使用合并的基因组DNA是一种方法;（2）为基因分型样本提供质量控制指标;（3）自动分析来自合并基因组样本的全基因组关联研究数据。

DESCRIPTION (provided by applicant): The technology to simultaneously genotype hundreds of thousands of single nucleotide polymorphisms (SNPs) in a single assay has only recently been developed and has the potential to revolutionize our ability to identify disease-associated genes in complex diseases. Specifically, high density SNP genotyping opens the possibility for case-control genome-wide association studies whereby SNPs that are evolutionary associated with a complex multigenic disease, and also in close physical proximity to a functional mutation, can be discovered. The major drawback of genome-wide association studies is that they require hundreds to thousands of cases and well matched controls for sufficient powering. This type of study is expected to cost millions of dollars using individual genotyping. The overall goal of this proposal is to develop cost effective design strategies and accompanying analysis tools for genome-wide case-control SNP association studies using pooled genomic DNA. We will develop new analysis tools and design strategies for genome-wide association studies using our unparalleled access to high-density genome-wide SNP genotyping data. Within the past six months, we have conducted genome-wide microarray SNP scans on over 5,000 samples. We are currently an early access site for the Affymetrix 500K Mapping array and have already completed two genome-wide scans on pooled DNA using this platform, verifying a previously known disease locus for Progressive Supranuclear Palsy (PSP) and identifying several new loci. We will have access to datasets from multiple genome-wide association studies on pooled genomic DNA including hypertension, Alzheimer's Disease (AD), autism, bipolar disorder, melanoma, PSP, memory, and diabetes. For AD, we will have access to both pooled and individual genotypes for 500K+ SNPs in 1,000 cases and 1,000 controls. Additionally, we have included funding within this proposal for genome-wide association studies on pooled genomic DNA for samples and diseases as decided by the steering community. In the course of this study, we will deliver web-based content and software tools that: (1) aid in the overall design of genome-wide association studies whereby using pooled genomic DNA is one approach; (2) provide quality control metrics for genotyped samples; and (3) automate analysis of a genome-wide association study data from pooled genomic samples.