MA Admixture Mapping Development & Application to NIDDM

MA 外加剂测绘开发

• 批准号: 7416787
• 负责人: Michael F. Seldin
• 金额: $ 42.66万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7416787
• 关键词: Admixture; African; African American; Algorithms; American; Asians; California; Case Study; Chinese American; Chinese People; Chromosomes; Cities; Communities; Complement; Complex; Control Groups; DNA; Data; Derivation procedure; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; European; Gene Frequency; Generations; Genes; Genome; Genotype; Hereditary Disease; Kidney Diseases; Location; Maps; Methods; Mexican; Mexican Americans; Mexico; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Phase; Population; Predisposition; Principal Investigator; Resources; Sampling; Science; Signal Transduction; Single Nucleotide Polymorphism; Structure; Study models; Susceptibility Gene; Testing; Texas; Validation; base; case control; density; design; diabetic; genetic linkage analysis; markov model; non-diabetic; programs; simulation; tool

DESCRIPTION (provided by applicant): Recently, substantial progress has been made in development and application of admixture mapping including derivation of appropriate statistical tools and testing in African American populations. The implementation of this approach in Mexican Americans (MA) has been hampered by the lack of a sufficient density of markers that can provide the ancestry information distinguishing the two major parental populations, Amerindians (Al) and European that contribute to this admixed population. The current proposal will remedy this problem by identification, validation and analysis of a panel of >5000 AI/European American (EA) Ancestry Informative Markers (AIMs) distributed over the genome. The panel of AIMs will be tested using a large collected set of MA DNA samples from type 2 diabetics with nephropathy (750 samples) or without nephropathy (600 samples) and a smaller matched set of nondiabetic MA subjects (300 samples). The utilization of this set will enable both case only and case control designs to be examined using a variety of recently developed algorithms. The first phase of the study (identification of AI/EA AIMs) will utilize an enrichment strategy based on pre-selecting AIMs dependent on putative Chinese/EA AIMs that have been identified in a completed 1.6 x 106 SNP screen. Over 23,000 putative Chinese/EA AIMs with Fsts > 0.45 have been identified and these will be used to examine 48 Pima Amerindian samples. Our previous studies conservatively suggest that >25% of these putative Chinese/EA AIMs will have an AI/EA Fst > 0.4. In the second phase > 5000 AI/EA AIMs will be chosen based on both Fst and chromosomal location to achieve a high density AIMs panel. This will be validated utilizing an additional set of 48 Pima Amerindians in addition to testing two other Al groups (96 samples each) and EA (96 samples). The MA populations will be examined using this panel that is expected to include >4000 validated EA/AI AIMs and analyzed to 1) define chromosomal segments derived from EA and Al, 2) perform modeling studies and 3) identify putative diabetes and diabetic nephropathy associated regions distinguishing the major ancestry. Finally, the three strongest signals will be further investigated utilizing a dense set of SNPs in the putative susceptibility regions.

描述（由申请人提供）：最近，在混合绘图的开发和应用方面取得了实质性进展，包括推导适当的统计工具和在非裔美国人群体中进行测试。这种方法在墨西哥裔美国人 (MA) 中的实施因缺乏足够密度的标记而受到阻碍，这些标记可以提供区分两个主要亲代群体的血统信息，即美洲印第安人 (Al) 和欧洲人，这两个群体构成了这一混合群体。目前的提案将通过识别、验证和分析分布在基因组上的超过 5000 个人工智能/欧美 (EA) 祖先信息标记 (AIM) 来解决这个问题。 AIM 组将使用来自患有肾病（750 个样本）或无肾病（600 个样本）的 2 型糖尿病患者的大量 MA DNA 样本以及一组较小的匹配的非糖尿病 MA 受试者（300 个样本）进行测试。该集的利用将使仅案例设计和案例控制设计能够使用各种最近开发的算法进行检查。研究的第一阶段（AI/EA AIM 的识别）将利用基于预先选择 AIM 的富集策略，该策略取决于已在完整的 1.6 x 106 SNP 筛选中识别的假定中国/EA AIM。超过 23,000 个 Fsts > 0.45 的假定中国/EA AIM 已被识别，这些将用于检查 48 个皮马美洲印第安人样本。我们之前的研究保守地表明，超过 25% 的假定中国/EA AIM 的 AI/EA Fst > 0.4。在第二阶段，将根据 Fst 和染色体位置选择 > 5000 个 AI/EA AIM，以实现高密度 AIM 组合。除了测试另外两个 Al 组（每组 96 个样本）和 EA（96 个样本）之外，还将利用另外一组 48 名皮马美洲印第安人对此进行验证。将使用该小组对 MA 群体进行检查，该小组预计将包括超过 4000 个经过验证的 EA/AI AIM，并进行分析以 1) 定义源自 EA 和 Al 的染色体片段，2) 进行建模研究，以及 3) 确定与假定的糖尿病和糖尿病肾病相关的区分主要祖先的地区。最后，将利用推定易感性区域中的一组密集 SNP 进一步研究三个最强信号。