Mapping T2DM Genes in GENNID Families

描述（由申请人提供）：令人信服的数据支持2型糖尿病（T2DM）的遗传基础，完成的基因组扫描表明至少有7个可能的易感区域。美国糖尿病协会（GENNID）于1993-2003年资助了一项多中心、多种族的研究，收集了T2DM基因图谱的主要资源，该研究包括6000多名个体，其中包括770名非裔美国人、1180名高加索人和1190名西班牙裔同胞对。其中不到1/3的资源进行了基因分型。我们建议使用0.6 cM单核苷酸多态性（SNP）图谱对所有样本进行全基因组扫描，以公开原始和清洁形式的基因型、谱系和表型数据，并利用该资源验证T2DM将以多个相互作用位点为特征的假设，其中一些位点是种族特异性的，而另一些位点则是跨种族的。5个特定目标将包括1)基因组扫描的样本和数据准备；2)利用多点受影响兄弟姐妹对方法分析基因组扫描数据，该方法应用于完整数据集和种族特异性数据，以及次要参数分析、有序子集分析和相互作用分析；3)在多达12个新区域中使用密集（100 kb） SNP图谱对连锁峰进行精细定位，并对精细图谱数据进行再分析；4)在初始cidr发布时，以及在清理或新数据分析的每个阶段，向所有感兴趣的糖尿病研究者分发初始和精细制图数据；5)定位候选基因，从公共数据库中选择标签snp，根据需要进行基因筛选，在每个连锁峰下寻找可能的易感基因。我们将使用密集SNP图测试基于家族的关联，并从GENNID家族和400-500对照中抽取400-500例不相关病例进行关联测试。这些研究将为未来确定已知候选基因的致病突变或使用连锁不平衡来确定其他T2DM易感位点的建议提供基础。拟议的研究将确定增加个体患2型糖尿病风险的特定基因，并将确定美国主要种族之间糖尿病患病率的显著差异是否可以部分解释为风险基因的不同频率。这些研究将确定在不同的种族群体中是否有不同的途径导致2型糖尿病，这反过来可能会导致针对特定遗传缺陷或种族特定途径的2型糖尿病的新疗法。

DESCRIPTION (provided by applicant): Compelling data support a genetic basis for type 2 diabetes (T2DM), and completed genome scans suggest at least 7 likely susceptibility regions. A major resource to map genes for T2DM was assembled in a multicenter, multiethnic study funded by the American Diabetes Association (GENNID) from 1993-2003 which comprises over 6000 individuals including 770 African-American, 1180 Caucasian, and 1190 Hispanic sib pairs. Under 1/3 of this resource has been genotyped. We propose a complete genome scan on all samples using a 0.6 cM single nucleotide polymorphism (SNP) map, to make the genotype, pedigree, and phenotypic data publicly available in both raw and cleaned forms, and to use this resource to test the hypothesis that T2DM will be characterized by multiple interacting loci, some that are ethnic-specific and others that will cross ethnic groups. The 5 Specific Aims will include 1) sample and data preparation for the genome scan; 2) analysis of the genome scan data using multipoint affected sib pair methods applied to both the full data set and ethnic-specific data, along with secondary parametric, ordered subset, and interaction analyses; 3) fine mapping of linkage peaks with dense (100 kb) SNP maps across up to 12 new regions and reanalysis of the fine map data; 4) distribution of initial and fine mapping data to all interested diabetes investigators upon initialCIDR release and at each stage of cleaning or new data analysis; and 5) a positional candidate gene search for likely susceptibility genes under each linkage peak by choosing tagSNPs from public databases and gene screening where needed. We will test for family based association using the dense SNP map, and for an association in 400-500 unrelated cases drawn from GENNID families and 400- 500 controls. These studies will provide the basis for future proposals to identify the causative mutations in known candidate genes or to use linkage disequilibrium to identify additional T2DM susceptibility loci. The proposed studies will identify the specific genes that increase an individual's risk of getting type 2 diabetes, and will determine whether striking differences in diabetes prevalence across major United States ethnic groups can be explained in part by different frequencies of risk genes. These studies will determine whether different pathways cause type 2 diabetes in different ethnic groups, which in turn may lead to new therapies for type 2 diabetes that may target specific genetic defects or ethnic-specific pathways.