Common Genetic Variation and Quantitative Diabetes Traits

描述（由申请人提供）：本次R 01 DK 78616更新的目标是识别新的 使用分阶段全基因组关联研究和荟萃分析（GWAS-MA），在一个大型跨四个种族样本（N~ 103，000：~ 26 K非裔美国人、~ 46 K欧洲人、~ 14 K西班牙人和~ 17 K亚洲人）中对2型糖尿病（T2 D）的数量性状（QT）基因座进行分析。在跨种族样本中，我们将进一步测试基因-环境和基因-基因相互作用和基因通路，并在纵向数据中，测试候选基因座的生理效应和T2 D预测。我们与其他NIDDK研究的联系为下一代测序（U 01 DK 085526）和遗传学预防T2 D临床应用试验（R21 DK 084527）提供了即时随访。最近美国T2 D的显著急剧增加，特别是在少数群体中，这是一个不断升级的临床和公共卫生挑战。遗传背景的变化加上肥胖的增加导致了美国T2 D的增加。在欧洲血统的人群中，大规模的GWAS-MA已经成功地概述了T2 D常见的遗传结构，由我们小组和我们的合作者领导的联盟研究最近贡献了超过50个新的T2 D风险或T2 D QT基因座。大型跨种族GWAS-MA是T2 D基因发现的关键下一步。具体目的是：1）在大型非糖尿病跨种族样本中使用GWAS-MA鉴定新型T2 D QT相关变体。我们假设：a）在大的非糖尿病非裔美国人样品中T2 D QT的分阶段GWAS-MA将鉴定与T2 D生理学和T2 D风险相关的新基因座，和B）将非裔美国人T2 D QT GWAS-MA与三个其它组联合用于大的跨四种族T2 D QT GWAS-MA将鉴定另外的基因座; 2）利用跨种族的大样本，通过基因-环境、基因-基因和基因通路分析，特别是SNP × BMI、体重变化，种族和其他相互作用者; 3)使用基于人群的纵向数据来阐明T2 D生理学随时间的演变，定义美国种族群体中风险的等位基因谱，并测试新的T2 D相关变异是否有助于T2 D风险预测。跨四个种族的GWAS-MA将为遗传发现，假设为T2 D及其相关QT基础的相互作用和途径的研究提供无与伦比的资源，并帮助更好地定义T2 D遗传学在生理靶向，人口预测和个性化预防方面的价值，以改善美国少数民族和非少数民族群体的健康。

DESCRIPTION (provided by applicant): The goal of this R01DK78616 renewal is to identify new type 2 diabetes (T2D) quantitative trait (QT) loci in a large trans-four-ethnic sample (N~103,000: ~26K African American, ~46K European, ~14K Hispanic and ~17K Asian) using staged genome-wide association studies with meta-analysis (GWAS-MA). In the trans- ethnic sample we will further test gene-environment and gene-gene interactions and gene pathways, and in longitudinal data, test candidate loci for physiological effects and for T2D prediction. Our links with other NIDDK studies offer immediate follow-up for next-generation sequencing (U01 DK085526) and trials of clinical application of genetics for T2D prevention (R21 DK084527). The significant recent, dramatic increase in T2D in the U.S., especially in minority groups, is an escalating clinical and public health challenge. Variation in genetic background coupled with increasing obesity accounts for rising T2D in the U.S.. In people of European ancestry, large-scale GWAS-MA have successfully outlined T2D common genetic architecture, with consortia studies led by our group and our collaborators recently contributing >50 new T2D risk or T2D QT loci. Large trans-ethnic GWAS-MA is a key next step in T2D gene discovery. Specific Aims are to: 1) Identify novel T2D QT-associated variants using GWAS-MA in large, non-diabetic, trans-ethnic samples. We hypothesize that: a) staged GWAS-MA of T2D QTs in a large non-diabetic African American sample will identify novel loci associated with T2D physiology and T2D risk and b) joining the African American T2D QT GWAS-MA with three other groups for a large trans-four-ethnic T2D QT GWAS-MA will identify additional loci; 2) Use the large trans-ethnic sample to find more loci, fine map, and suggest mechanism by tests of gene-environment, gene-gene and gene pathway analyses, specifically, accounting for SNP x BMI, weight change, ethnicity and other interactors; and 3) Use longitudinal population-based data to iluminate the evolution of T2D physiology over time, define the allelic spectrum of risk in U.S. ethnic groups, and test if novel T2D-related variants aid T2D risk prediction. The trans-four-ethnic GWAS-MA will provide an unparalleled resource for genetic discovery, studies of interactions and pathways hypothesized to underlie T2D and its related QTs, and help better define the value of T2D genetics for physiological targeting, population prediction and personalized prevention to improve health in minority and non-minority groups the U.S..