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(申请人提供)：混合作图是筛选基因组中疾病基因的一种新方法。它与传统的基于单倍型的关联研究一样强大，但在今天是实用的，因为它只需要研究几千个多态遗传标记。混合图谱的想法是，最近混合种族群体的后代患有疾病的人应该有更高的可能性从疾病风险更高的祖先群体中遗传DNA。例如，由于美洲印第安人血统与2型糖尿病的关联，平均有30%的美洲印第安人血统和70%的欧洲血统的拉美裔美国人可能倾向于在T2D基因附近具有异常高的美国印第安人血统水平。我们最近创建了第一个用于非裔美国人混合图谱的实用资源，并开发了嵌套在马尔可夫链蒙特卡罗中的隐马尔可夫模型来分析混合扫描的数据，并将其应用于定位多发性硬化症的风险基因。我们现在建议为美洲印第安人混合人群创建一个实用的混合地图，并使用它来研究来自哥伦比亚安蒂奥基亚的600例2型糖尿病患者和250名对照。我们将通过搜索公司数据库开始这项研究，该数据库包含156万个单核苷酸多态(SNPs)，这些SNPs在美洲印第安人和欧洲裔美国人中都有已知的频率。然后，我们将在实验室对来自美洲印第安人、欧洲裔美国人和非洲人的377个样本中的4608个SNPs进行验证。在此验证基因分型的基础上，我们将选择大约1,536个标记的子集，这些标记对于混合作图具有最大的信息量。这组记号笔将构成我们的拉丁裔混血儿“地图”。作为这项应用的第二个目标，我们将使用该图谱来测量600例2型糖尿病患者和250名来自哥伦比亚的匹配对照的基因组祖先。这些病例都进行了广泛的2型糖尿病相关特征的表型鉴定。使用我们的图谱，我们将扫描基因组，在2型糖尿病病例中寻找异常高(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。这项先导性研究将首次应用我们的混合图谱，有可能发现新的2型糖尿病风险基因。这项研究还将使对数千名2型糖尿病患者进行更大规模的混合物图谱研究成为可能，我们希望在美国拉丁裔和拉丁美洲人群中进行这一研究。