Mapping T2DM Genes in GENNID Families

Compelling data support a genetic basis for type 2 diabetes (T2DM), and completed genome scans suggest 至少 7 个可能的易感区域。 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 同胞对。该资源中不到 1/3 已进行基因分型。我们建议对所有患者进行完整的基因组扫描 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 假设 T2DM 的特征是多个相互作用的基因座，其中一些是种族特异性的， 其他将跨越种族群体。 The 5 Specific Aims will include 1) sample and data preparation for the 基因组扫描； 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 分析； 3) fine mapping of linkage peaks with dense (100 kb) SNP maps across up to 12 new regions and 精细地图数据的重新分析； 4) distribution of initial and fine mapping data to all interested diabetes 初始 CIDR 发布以及清理或新数据分析的每个阶段的调查员； 5) 位置 通过选择 tagSNP，在每个连锁峰下候选基因搜索可能的易感基因 public databases and gene screening where needed.我们将使用以下方法测试基于家庭的关联 密集的 SNP 图，以及来自 GENNID 家族的 400-500 个不相关病例和 400- 500 个控制。这些研究将为未来确定致病突变的建议提供基础。 known candidate genes or to use linkage disequilibrium to identify additional T2DM susceptibility loci.的 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的糖尿病患病率是否存在显着差异 不同的群体可以部分地通过风险基因的不同频率来解释。这些研究将决定是否 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.

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.