Mapping T2DM Genes in GENNID Families

令人信服的数据支持2型糖尿病（T2 DM）的遗传基础，完成的基因组扫描表明 至少7个可能的易感区域。T2 DM基因图谱的主要资源是在一个 1993-2003年由美国糖尿病协会（GENNID）资助的多中心、多种族研究 其中包括6000多人，包括770名非洲裔美国人，1180名白人和1190名西班牙裔美国人。 同胞对。不到1/3的资源已被基因分型。我们建议对所有的 使用0.6 cM单核苷酸多态性（SNP）图谱对样本进行分析，以确定基因型、谱系和 表型数据以原始和清洁的形式公开提供，并使用此资源来测试 假设T2 DM的特征是多个相互作用的基因座，有些是种族特异性的， 另一些则是跨种族的。5个具体目标将包括：1）样本和数据准备 基因组扫描; 2）使用多点受影响的同胞对方法分析基因组扫描数据， 完整的数据集和特定种族的数据，沿着次要参数、有序子集和相互作用 分析; 3）在多达12个新区域上用密集（100 kb）SNP图谱精细定位连锁峰， 精细标测数据的再分析; 4）将初始和精细标测数据分配给所有感兴趣的糖尿病患者 在初始CIDR发布时以及在清理或新数据分析的每个阶段， 候选基因搜索每个连锁峰下可能的易感基因，通过选择tagSNPs从 公共数据库和基因筛查。我们将测试基于家庭的关联使用 密集的SNP图谱，以及来自GENNID家族的400-500例无关病例和400- 500个控制器。这些研究将为今后提出鉴定致病突变的建议提供基础， 已知的候选基因或使用连锁不平衡来鉴定其他T2 DM易感基因座。的 拟议中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糖尿病患病率的显著差异是否 不同群体的风险基因频率不同可以部分解释。这些研究将确定是否 不同的途径导致不同种族的2型糖尿病，这反过来可能导致新的治疗方法 针对2型糖尿病，可能针对特定的遗传缺陷或种族特异性途径。

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 susceptiblity 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.