Admixture Mapping to Identify T2DM Genes in African Americans

描述（由申请人提供）：2型糖尿病是一个主要的临床和公共卫生问题，特别是在非洲裔美国人中。本申请的总体目标是鉴定新的基因座，其可以部分地解释与白人相比非裔美国人中2型糖尿病的过度风险。我们将采用混合物连锁不平衡作图（MALD）分析，一种特殊形式的连锁不平衡作图，在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研究是一项基于社区的动脉粥样硬化自然史前瞻性队列研究。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人ARIC参与者（N = 1，238），对照将是1，238名年龄匹配的非裔美国人ARIC参与者，没有2型糖尿病。我们假设，2型糖尿病的一些易感等位基因是目前在非洲裔美国人比白人的频率更高，在非洲裔美国人的基因组的特定区域包含标记等位基因，在混合物连锁不平衡与2型糖尿病易感等位基因。为了验证这一假设，我们将：（1）对1,536个高度信息化的非裔美国人MALD标记进行基因分型使用遗传性疾病研究中心（CIDR）人类定制单核苷酸多态性（SNP）基因分型设施，对2，476名非洲裔美国人ARIC参与者的DNA（~2 cM平均间距）进行分析;（2）使用上述扫描进行全基因组MALD分析以鉴定与2型糖尿病处于混合连锁不平衡的区域;以及（3）追踪并确认最有希望的具有更密集间隔的SNP的推定染色体区域。拟议的遗传分析是创新的，补充了更传统的连锁和候选基因技术。首席研究员组建了一个专家小组，负责这项研究的所有组成部分。本申请探讨了MALD，一种新的映射技术，以确定2型糖尿病易感基因的效用。虽然这种方法风险很高，但它也为未来2型糖尿病和其他复杂性状的遗传学研究带来了很大希望。2型糖尿病易感基因的检测是一个艰巨的挑战。这项研究的结果不仅将为基因定位的新方法提供关键见解，而且还将导致更好地了解控制2型糖尿病易感性的基因，这是一个在非洲裔美国人中具有高度相关性的问题。

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.