Building a Latino admixture map & pilot study to find Type 2 Diabetes risk

构建拉丁裔混合图

• 批准号: 7146551
• 负责人: David E Reich
• 金额: $ 26万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146551
• 关键词: African; Hispanic Americans; Native Americans; South American; biotechnology; caucasian American; diabetes risk; genetic mapping; genetic markers; genetic polymorphism; genetic susceptibility; genotype; human data; noninsulin dependent diabetes mellitus; population genetics

DESCRIPTION (provided by applicant): Admixture mapping is a novel way to screen the genome for disease genes. It has as much power as a traditional haplotype-based association study, but is practical today, because it requires studying only a couple of thousand polymorphic genetic markers. The idea of admixture mapping is that people with disease who descend from the recent mixing of ethnic groups should have an increased probability of inheriting DNA from the ancestral population with higher disease risk. For example, because of the association of Amerindian ancestry with Type 2 diabetes, Latino Americans who have 30% Amerindian and 70% European ancestry on average might tend to have an unusually high level of Amerindian ancestry near a T2D gene. We recently created the first practical resource for admixture mapping in African Americans, and developed a Hidden Markov Model nested within a Markov Chain Monte Carlo to analyze data from admixture scans, and applied it to localize a risk gene for multiple sclerosis. We now propose to create a practical admixture map for Amerindian mixed populations, and to use it to study Type 2 Diabetes in 600 cases and 250 controls from Antioquia, Colombia. We will begin this study by searching a company database of 1.56 million single nucleotide polymorphisms (SNPs) with known frequencies in populations of both Amerindian and European American descent. We will then validate 4,608 of these SNPs in our laboratory in 377 samples drawn from Amerindian, European American, and African populations. Based on this validation genotyping, we will then select a subset of about 1,536 markers that are maximally informative for admixture mapping. This panel of markers will constitute our Latino admixture 'map'. As the second goal of this application, we will use the map to measure ancestry along the genome in 600 Type 2 diabetes cases, and 250 matched controls from Colombia. The cases have all been extensively phenotyped for a range of Type 2 Diabetes-related traits. Using our map, we will scan the genome to look for regions of unusually high (or low) Amerindian ancestry in the Type 2 Diabetes cases, which could indicate the presence of a diabetes risk gene. This pilot study will provide a first application of our admixture map, with potential to find new risk genes for Type 2 Diabetes. The study will also enable larger admixture mapping studies with many thousands of patients with Type 2 Diabetes, which we would like to pursue both in U.S. Latino and in Latin American populations.

描述（由申请人提供）：混合映射是筛选疾病基因基因组的新方法。它具有与传统基于单倍型的关联研究一样多的功能，但如今是实用的，因为它只需要研究数千种多态性遗传标记。混合映射的想法是，疾病的患者从最近的种族混合中降低，应该增加从疾病风险较高的祖先人群中遗传DNA的可能性。例如，由于美洲印第安人血统与2型糖尿病的关系，平均拥有30％的美洲印第安人和70％欧洲血统的拉丁裔美国人可能在T2D基因附近具有异常高的美洲印第安人血统。我们最近创建了第一个用于非裔美国人混合映射的实用资源，并开发了一个嵌套在马尔可夫链蒙特卡洛中的隐藏的马尔可夫模型，以分析混合扫描中的数据，并将其应用于多发性硬化症的风险基因。现在，我们建议为美洲混合群体创建一个实用的混合图，并使用它在600例中研究2型糖尿病，并从哥伦比亚Antioquia中进行250个对照。我们将通过搜索156万个单核苷酸多态性（SNP）的公司数据库开始这项研究。然后，我们将在来自美国，欧美和非洲人口的377个样品中验证377个样本中的4,608个SNP。然后，基于此验证基因分型，我们将选择约1,536个标记的子集，这些标记在混合映射方面具有最大信息。这个标记面板将构成我们的拉丁裔混合物“地图”。作为该应用程序的第二个目标，我们将使用该地图在600种2型糖尿病病例中测量沿基因组的祖先，以及哥伦比亚的250个匹配的对照。这些病例都针对一系列与2型糖尿病相关的特征进行了广泛的表型。使用我们的地图，我们将扫描基因组，以寻找2型糖尿病病例中异常高（或低）美洲印第安人血统的区域，这可能表明存在糖尿病风险基因。这项试点研究将为我们的混合图提供首次应用，并有可能找到2型糖尿病的新风险基因。这项研究还将为数千名2型糖尿病患者提供更大的混合映射研究，我们想在美国拉丁裔和拉丁美洲人群中进行。