MA Admixture Mapping Development & Application to NIDDM

描述（由申请人提供）：最近，在混合物图谱的开发和应用方面取得了实质性进展，包括导出适当的统计工具和在非裔美国人人群中进行测试。这种方法在墨西哥裔美国人（MA）中的实施受到了阻碍，因为缺乏足够密度的标记物，这些标记物可以提供区分两个主要亲本群体（美洲印第安人（Al）和欧洲人）的祖先信息，这两个主要亲本群体对该混合群体有贡献。目前的提议将通过鉴定、验证和分析分布在基因组上的一组>5000个AI/欧洲美洲（EA）生物学信息标记（AIM）来解决这个问题。将使用从2型糖尿病伴肾病（750份样本）或不伴肾病（600份样本）患者中采集的大量MA DNA样本集和较小的非糖尿病MA受试者匹配集（300份样本）对AIM组进行检测。这一套的利用将使案件和案件控制的设计进行检查，使用各种最近开发的算法。研究的第一阶段（AI/EA AIM的鉴定）将采用基于预先选择AIM的富集策略，该策略依赖于已在完成的1.6 x 106 SNP筛选中鉴定的推定中国/EA AIM。已经确定了超过23，000个Fsts > 0.45的推定中国/EA AIM，这些将用于检查48个皮马美洲印第安人样本。我们先前的研究保守地表明，这些推定的中国/EA AIM中有>25%的AI/EA Fst > 0.4。在第二阶段，将基于Fst和染色体位置选择> 5000个AI/EA AIM，以实现高密度AIM组。除了测试另外两个Al组（每组96件样品）和EA组（96件样品）外，还将使用另外一组48名皮马美洲印第安人进行确认。将使用预期包括>4000个经验证的EA/AI AIM的该组来检查MA群体，并进行分析以1）定义源自EA和Al的染色体区段，2）进行建模研究，以及3）鉴定区分主要祖先的推定糖尿病和糖尿病肾病相关区域。最后，三个最强的信号将进一步研究利用一组密集的SNP在推定的易感性区域。

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.