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，完整的基因组扫描表明 至少7个可能的易感区域。一个定位T2 DM基因的主要资源被组装在一个 1993-2003年由美国糖尿病协会(GENNID)资助的多中心、多种族研究 它由6000多人组成，其中包括770名非裔美国人，1180名高加索人和1190名西班牙人 SIB对。不到1/3的资源已经进行了基因分型。我们建议对所有人进行完整的基因组扫描 样本使用0.6 cM的单核苷酸多态(SNP)图谱，以制作基因、系谱和 公开提供原始形式和已清理形式的表型数据，并使用此资源测试 假设T2 DM将由多个相互作用的基因座表征，其中一些是种族特有的 其他人将跨越种族群体。5个具体目标将包括1)样本和数据准备 基因组扫描；2)使用多点影响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，以及次要参数、有序子集和交互 分析；3)利用高密度(100 Kb)SNP图谱精细定位连锁峰，覆盖多达12个新区域和 重新分析精细图谱数据；4)将初始和精细图谱数据分配给所有感兴趣的糖尿病 调查人员在最初CIDR发布时以及在清理或新数据分析的每个阶段；以及5)位置 候选基因通过选择标签SNPs在每个连锁高峰下搜索可能的感病基因 公共数据库和必要的基因筛查。我们将使用 密集的SNP图谱，以及来自GENNID家族的400-500个无关病例和400-500个 500个控制点。这些研究将为将来提出识别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识别额外的T2 DM易感基因。这个 拟议中的研究将确定增加个人患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 风险基因的不同频率可以在一定程度上解释群体。这些研究将确定 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 对于2型糖尿病，可能针对特定的遗传缺陷或种族特定的途径。

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.