Admixture Mapping Development and Testing in AA SLE

描述（由申请人提供）：混合图谱是在复杂遗传疾病中发现疾病易感基因的潜在强大工具。该方法依赖于易感基因分布存在差异的不同族群之间的近期杂交，并可在杂交人群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权力和基于关联的方法，难以应用于全基因组。为了证明外加剂作图的适用性，有必要1)确定一组区分祖先的标记；2)开发和应用多位点统计检验，在存在祖先关联的情况下进行连锁，模拟真实的基因分型数据；3)在实际疾病中提供该方法的实际演示。这些是这项建议的主要目标。我们小组以及其他研究人员的初步研究表明，非裔美国人是一个大的混合人口，混合测绘可能适用于此。流行病学研究表明，系统性红斑狼疮是一种不成比例地影响非洲血统个体的疾病。初步研究表明，祖先信息标记（AIMs）可以确定非洲和欧洲血统，并且与其他标记相比，绝大多数这些AIMs在欧洲和非洲创始人群中只有很小的种族内差异。

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.