Admixture Mapping to Identify T2DM Genes in African Americans

描述(申请人提供)：2型糖尿病是一个主要的临床和公共卫生问题，特别是在非裔美国人中。这项申请的总体目标是确定可能部分解释非裔美国人与白人相比患2型糖尿病风险过高的新基因。我们将使用连锁不平衡图谱的一种特殊形式--混合物连锁不平衡(MALD)分析，在一项嵌套在社区动脉粥样硬化风险(ARIC)研究中的病例对照研究中进行全基因组MALD分析，ARIC研究是一项关于动脉粥样硬化自然历史的社区前瞻性队列研究。对于拟议的MALD分析，病例将是所有患有2型糖尿病的非裔美国ARIC参与者(N=1238)，对照组将是1238名年龄匹配的没有2型糖尿病的非裔美国ARIC参与者。我们假设，一些2型糖尿病的易感基因在非裔美国人中的出现频率高于白人，并且非裔美国人基因组的特定区域包含与2型糖尿病易感基因处于混合连锁不平衡的标记等位基因。为了验证这一假设，我们将：(1)使用遗传病研究中心(CIDR)人类定制单核苷酸多态性(SNP)基因分型工具对2,476名非裔美国人ARIC患者的DNA中1,536个信息量高的非裔美国人MALD标记(平均间距约2 cM)进行基因分型；(2)使用上述扫描进行全基因组MALD分析，以确定与2型糖尿病处于混合连锁不平衡的区域；以及(3)跟踪并确认SNPs分布更密集的最可能的染色体区域。拟议的遗传分析是创新的，是对更传统的连锁和候选基因技术的补充。首席调查员组建了这项研究的所有组成部分的专家小组。这项应用探索了MALD，一种新的作图技术，用于识别2型糖尿病易感基因。尽管这种方法风险很高，但它也为未来2型糖尿病和其他复杂特征的遗传学研究带来了很大希望。检测2型糖尿病的易感基因是一项艰巨的挑战。这项研究的发现不仅将为绘制基因图谱的新方法提供关键的见解，还将有助于更好地理解控制2型糖尿病易感性的基因，这是一个与非裔美国人高度相关的问题。

DESCRIPTION (provided by applicant): Type 2 diabetes is a major clinical and public health problem, especially in African Americans. The overall objective of this application is to identify novel loci that may partially account for excess risk of type 2 diabetes in African Americans compared to whites. We will employ Mapping by Admixture Linkage Disequilibrium (MALD) analysis, a specialized form of linkage disequilibrium mapping, to perform a genome-wide MALD analysis in a case-control study nested within the Atherosclerosis Risk in Communities (ARIC) study, a community-based prospective cohort study of the natural history of atherosclerosis. For the proposed MALD analysis, cases will be all African-American ARIC participants with type 2 diabetes (N = 1,238), and controls will be 1,238 age-matched African-American ARIC participants without type 2 diabetes. We hypothesize that some susceptibility alleles for type 2 diabetes are present at a higher frequency in African Americans than in whites and that specific regions of the genome in African Americans contain marker alleles that are in admixture linkage disequilibrium with type 2 diabetes susceptibility alleles. To test this hypothesis, we will: (1) genotyping 1,536 highly informative African-American MALD markers (~2 cM average spacing) in DNA from 2,476 African-American ARIC participants using the Center for Inherited Disease Research (CIDR) Human Custom Single Nucleotide Polymorphism (SNP) Genotyping Facility; (2) perform a genome-wide MALD analysis using the aforementioned scan to identify regions that are in admixture linkage disequilibrium with type 2 diabetes; and (3) follow up and confirm the most promising putative chromosomal regions with more densely-spaced SNPs. The proposed genetic analyses are innovative and complementary to the more traditional linkage and candidate gene techniques. The Principal Investigator has assembled a team of experts in all components of this research. This application explores the utility of MALD, a novel mapping technique, to identify type 2 diabetes susceptibility genes. Although this methodology is high risk, it also holds high promise for future genetics studies of type 2 diabetes and other complex traits. Detection of susceptibility genes for type 2 diabetes is a daunting challenge. Findings from this study will not only provide key insights into a new methodology for mapping genes, but will also lead to a better understanding of the genes that control type 2 diabetes susceptibility, a problem with high relevance in African Americans.