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

使用混合基因组 DNA 进行多阶段关联研究的设计和分析

• 批准号: 7104769
• 负责人: Dietrich A Stephan
• 金额: $ 37万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104769
• 关键词: DNA; Internet; automated data processing; computer program /software; computer system design /evaluation; cooperative study; gene expression; gene mutation; genetic screening; genotype; human data; linkage mapping; microarray technology; quantitative trait loci; single nucleotide polymorphism; statistics /biometry

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.

描述（由申请人提供）：同时基因型的技术直到最近才开发出一个单个测定中的数十万个单核苷酸多态性（SNP），并且有可能彻底改变我们鉴定复杂疾病中与疾病相关基因的能力。具体而言，高密度SNP基因分型为整个病例对照基因组关联研究开辟了可能性，从而可以发现与复杂的多基因疾病相关的SNP，并且可以发现与功能突变的物理近端相关的SNP。全基因组关联研究的主要缺点是，它们需要数百至数千个病例和匹配的控制才能充分供电。这种研究预计使用单个基因分型将耗资数百万美元。该提案的总体目标是使用合并的基因组DNA制定针对全基因组病例对照的SNP协会研究的成本有效设计策略和随附的分析工具。 我们将使用我们无与伦比的高密度基因组SNP基因分型数据的访问来为全基因组关联研究开发新的分析工具和设计策略。在过去的六个月中，我们对超过5,000个样品进行了全基因组微阵列SNP扫描。目前，我们是Affymetrix 500K映射阵列的早期访问地点，并已经使用该平台在合并的DNA上完成了两次全基因组扫描，验证了先前已知的疾病基因座，用于进行性疾病的疾病基因座（PSP）并识别出几个新的位点。我们将可以访问有关综合基因组DNA的多个基因组关联研究的数据集，包括高血压，阿尔茨海默氏病（AD），自闭症，双相情感障碍，黑色素瘤，PSP，记忆，记忆和糖尿病。对于AD，我们将在1,000例和1,000个对照中访问500K+ SNP的合并和单个基因型。此外，我们还将基因组综合研究的基因组基因组DNA研究的资金包括在指导群落决定的样品和疾病的合并基因组DNA研究中。在本研究的过程中，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，从而使用汇总基因组DNA是一种方法； （2）为基因分型样品提供质量控制指标； （3）自动分析来自汇总基因组样品的全基因组关联研究数据。