Admixture Mapping Development and Testing in AA SLE

描述(申请人提供)：混合作图是在复杂遗传病中寻找疾病易感基因的潜在的有力工具。该方法依赖于不同民族之间最近的混杂，不同民族之间存在易感基因分布的差异，并且可以在混杂人口中区分染色体区域的祖先。我们相信，这种方法将是对全基因组连锁研究的有益补充，因为全基因组连锁研究往往缺乏能力和基于关联的方法，而这些方法很难在全基因组范围内应用。为了提供混合作图适用性的证据，有必要1)识别一组区分祖先的标记；2)开发和应用在存在祖先关联的情况下的连锁的多位点统计检验，以模拟真实的基因分型数据；以及3)在真实疾病中提供该方法的实际演示。这些是这项提案的主要目标。我们小组以及其他研究人员的初步研究表明，非裔美国人是一个很大的混杂群体，混杂映射可能适用于这一群体。流行病学研究表明，系统性红斑狼疮是一种对具有非洲血统的人影响不成比例的疾病。初步研究表明，血统信息标记(AIMS)可以识别非洲人和欧洲人的血统，而且与其他标记相比，绝大多数AIMS在欧洲和非洲创始人口中只有很小的种族内差异。 此外，包括世俗科学筛选在内的几个小组目前的结果表明，超过160万个SNPs表明，现在有足够大的全基因组AIMS集可用于强有力的统计分析。这项提议将建立一套全基因组的&gt；4000目标，其特点是在非洲人、欧洲美国人和非裔美国人群体中。对950例非裔美国人SLE病例和500名匹配的非裔美国人对照进行分型，将为模拟和测试提供必要的数据，并将有机会探索这种方法对一种对非裔美国人健康至关重要的疾病的有效性。

DESCRIPTION (provided by applicant): Admixture mapping is a potentially powerful tool for finding disease susceptibility genes in complex genetic diseases. The method depends on recent admixture between different ethnic groups for which differences in the distribution of susceptibility genes exist, and ancestry of the chromosomal regions can be distinguished in the admixed population. We believe that this approach will be a useful complement to genome-wide linkage studies that often lack power and association based methodologies that are difficult to apply genome-wide. For providing proof of the applicability of admixture mapping it is necessary to 1) identify a set of markers that distinguish ancestry; 2) develop and apply multilocus statistical tests for linkage in the presence of ancestral association to simulations of real genotyping data; and 3) provide an actual demonstration of the method in a real disease. These are the major objectives of this proposal. Preliminary studies by our group as well as other investigators have shown that African Americans are a large admixed population for which admixture mapping is likely to be applicable. Epidemiological studies suggest that systemic lupus erythematosus is a disease that disproportionately affects individuals with African heritage. Preliminary studies provide confidence that a Ancestry Informative Markers (AIMs) can identify African versus European ancestry and that the vast majority of these AIMs in contrast to other markers have only small intra-ethnic differences within the European and African founding populations. Furthermore, the current results of several groups including the Perlegen Sciences screen of over 1.6 million SNPs suggest that a sufficiently large genome-wide set of AIMs is now available for a robust statistical analysis. This proposal will establish a genome wide set of >4000 AIMs that are characterized in African, European American, and African American populations. The typing of 950 African American SLE cases and 500 matched African American controls will provide the necessary data for simulations and testing as well as the opportunity to explore the usefulness of this method for a disease of major importance to the health of African Americans.