MA Admixture Mapping Development & Application to NIDDM

描述（由申请人提供）：最近，混合测绘的发展和应用取得了实质性进展，包括推导适当的统计工具和在非裔美国人群体中的测试。这种方法在墨西哥裔美国人（MA）中的实施受到了阻碍，因为缺乏足够的标记密度，无法提供区分两个主要亲本群体的祖先信息，即构成这种混合群体的美洲印第安人（Al）和欧洲人。目前的提案将通过鉴定、验证和分析分布在基因组上的5000个AI/欧美（EA）祖先信息标记（AIMs）来解决这一问题。AIMs小组将使用大量收集的2型糖尿病肾病患者（750个样本）或无肾病患者（600个样本）的MA DNA样本和较小匹配的非糖尿病MA受试者（300个样本）进行测试。这一组的利用将使案例和案例控制设计都可以使用各种最近开发的算法进行检查。研究的第一阶段（AI/EA AIMs的鉴定）将采用基于预选择AIMs的富集策略，该策略依赖于已完成的1.6 x 106 SNP筛选中鉴定的假定的中国/EA AIMs。已经确定了超过23,000个假定的中国/EA目标，Fsts为0.45，这些目标将用于检查48个皮马美洲印第安人样本。我们之前的研究保守地认为，这些假定的中国/EA AIMs中，有25%的AI/EA将达到> 0.4。在第二阶段，将根据第一个和染色体位置选择bbb5000个AI/EA AIMs，以实现高密度AIMs面板。除了测试另外两个人工智能组（每个组96个样本）和EA组（96个样本）外，还将使用另外48个皮马美洲印第安人组进行验证。MA人群将使用该小组进行检查，该小组预计将包括4000个经过验证的EA/AI AIMs，并分析1)定义来自EA和Al的染色体片段，2)进行建模研究，3)确定推定的糖尿病和糖尿病肾病相关区域，以区分主要祖先。最后，三个最强的信号将进一步研究利用密集的单核苷酸多态性在假定的易感区域。

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.