MA Admixture Mapping Development & Application to NIDDM

描述(由申请人提供)：最近，混合绘图的开发和应用取得了实质性进展，包括在非裔美国人人口中得出适当的统计工具和测试。这一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来提供祖先信息，以区分造成这一混杂群体的两个主要亲本群体--美洲印第安人(Al)和欧洲人。目前的建议将通过识别、验证和分析分布在基因组上的一组&gt；5000 AI/欧洲美洲人(EA)祖先信息标记(AIMS)来解决这个问题。AIMS小组将使用从有肾病的2型糖尿病患者(750个样本)或没有肾病的2型糖尿病患者(600个样本)收集的大量MA DNA样本，以及较小匹配的非糖尿病MA受试者(300个样本)进行测试。这一集合的利用将使仅病例和病例对照设计都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目标的识别)将利用基于预选目标的丰富策略，这些目标依赖于假定的中国/EA目标，这些目标已在完成的1.6×106 SNP筛查中确定。超过23,000个假定的中国/EA目标与Fst&gt；0.45；已经确定，这些将被用来检查48个PIMA美国印第安人样本。我们之前的研究保守地认为，在这些推定的中文/EA目标中，有25%将有AI/EA Fst&gt；0.4。在第二阶段，将根据FST和染色体位置选择&gt；5000个AI/EA AIMS，以实现高密度AIMS面板。除了测试另外两个Al组(每个组96个样本)和EA(96个样本)之外，还将使用另外48个PIMA美洲印第安人组来验证这一点。MA人群将使用这个小组进行检查，该小组预计将包括&gt；4000个经过验证的EA/AI靶标，并进行分析，以1)定义源自EA和A1的染色体片段，2)进行建模研究，以及3)识别与主要祖先相区别的推定糖尿病和糖尿病肾病相关区域。最后，将利用假定易感区域中密集的SNPs集来进一步研究三个最强的信号。

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.