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: 7452403
• 负责人: David W Craig
• 金额: $ 35.93万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7452403
• 关键词: Alzheimer' s Disease; Autistic Disorder; Biological Assay; Bipolar Disorder; Communities; Complex; Computer software; DNA; Data; Data Set; Diabetes Mellitus; Disease; Experimental Designs; Funding; Gene Frequency; Genes; Genome; Genomics; Genotype; Goals; Haplotypes; Hypertension; Individual; Informatics; Internet; Linkage Disequilibrium; Maps; Measurement; Memory; Memory Disorders; Meta-Analysis; Metric; Mutation; Noise; Online Systems; Paralysed; Progressive Supranuclear Palsy; Quality Control; Recommendation; Research Design; Sampling; Scanning; Signal Transduction; Single Nucleotide Polymorphism; Site; Software Tools; Staging; Structure; System; Technology; case control; cost; cost effective; density; design; genome wide association study; markov model; melanoma; open source; software development; tool; web-accessible

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)：在一次测试中同时对数十万个单核苷酸多态(SNP)进行分型的技术是最近才开发出来的，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。具体地说，高密度SNP基因分型为病例对照全基因组关联研究提供了可能性，从而可以发现与复杂的多基因疾病进化相关的SNP，并且可以发现与功能突变物理上非常接近的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获得足够的动力。这种类型的研究预计将耗资数百万美元，使用个人基因分型。这项建议的总体目标是开发具有成本效益的设计策略和附带的分析工具，用于使用汇集的基因组DNA进行全基因组病例对照SNP关联研究。 我们将利用我们无与伦比的高密度全基因组SNP基因分型数据，为全基因组关联研究开发新的分析工具和设计策略。在过去的六个月里，我们已经对5000多个样本进行了全基因组微阵列SNP扫描。我们目前是Affymetrix 500K映射阵列的早期访问站点，并已使用该平台完成了对池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)的疾病基因座，并识别了几个新的基因座。我们将可以访问多个基因组范围研究的数据集，这些研究涉及汇集的基因组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，我们将能够获得1,000例患者和1,000名对照中500K+SNPs的汇集和单独基因型别。此外，我们还根据指导社区的决定，在这项提案中包括了对样本和疾病的基因组DNA池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，其中使用汇集的基因组DNA是一种方法；(2)为基因分型样本提供质量控制度量；以及(3)自动分析来自汇集的基因组样本的全基因组关联研究数据。

项目成果

Identification of genetic variants using bar-coded multiplexed sequencing.

• DOI: 10.1038/nmeth.1251
• 发表时间: 2008-10
• 期刊: NATURE METHODS
• 影响因子: 48
• 作者: Craig, David W.;Pearson, John V.;Szelinger, Szabolcs;Sekar, Aswin;Redman, Margot;Corneveaux, Jason J.;Pawlowski, Traci L.;Laub, Trisha;Nunn, Gary;Stephan, Dietrich A.;Homer, Nils;Huentelman, Matthew J.
• 通讯作者: Huentelman, Matthew J.

Statistical comparison framework and visualization scheme for ranking-based algorithms in high-throughput genome-wide studies.

高通量全基因组研究中基于排名的算法的统计比较框架和可视化方案。

• DOI: 10.1089/cmb.2008.0151
• 发表时间: 2009
• 期刊: Journal of computational biology : a journal of computational molecular cell biology
• 作者: Tembe,WaibhavD;Pearson,JohnV;Homer,Nils;Lowey,James;Suh,Edward;Craig,DavidW
• 通讯作者: Craig,DavidW

Resolving individuals contributing trace amounts of DNA to highly complex mixtures using high-density SNP genotyping microarrays.

• DOI: 10.1371/journal.pgen.1000167
• 发表时间: 2008-08-29
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Homer N;Szelinger S;Redman M;Duggan D;Tembe W;Muehling J;Pearson JV;Stephan DA;Nelson SF;Craig DW
• 通讯作者: Craig DW