Multiethnic Study of Type 2 Diabetes Genes

描述（由申请人提供）：2型糖尿病（T2D）具有复杂的遗传，表明多重遗传DNA变异的因果作用。全基因组关联研究（GWAS）现在已经绘制了20多个新的基因座，其中常见变异与T2D风险相关。尽管取得了这一进展，但已确定的风险等位基因对T2D风险的总体变化解释相对较少。为了充分了解T2D的遗传结构，我们需要从基因座到基因，以查明与观察到的关联有关的特定因果基因。我们需要解决等位异基因。其中T2D基因可能有多种不同的常见和罕见突变。我们需要探索种族差异，其中导致T2D的基因突变的特定补体可能在不同种族的频率和效应大小上有所不同。我们假设：(1)GWAS鉴定的每个区域包含至少一个T2D致病基因，受至少一个常见功能变异的影响；(2)除了GWAS确定的指数变异外，每个基因座中还有一个或多个其他常见变异影响T2D；(3)除了常见变异外，每个基因都可能含有更强烈影响T2D风险的罕见突变，(4)这些变异的特征、频率和影响在美国人口的多个种族群体中各不相同。为了解决这些假设，我们提出了三个具体目标。(1)汇集来自杰克逊心脏研究、弗雷明汉心脏研究、多种族队列研究和糖尿病预防项目的具有代表性的美国人口的多种族样本，共包括-29,000名具有T2D表型和DNA的个体；(2)利用我们的多民族设计和来自1000基因组计划的新兴数据，确定并精细绘制每个族群中每个位点的共同变异；(3)通过对每个族群的所有编码外显子进行深度测序，确定每个位点上罕见的因果突变。共同研究者在复杂疾病遗传学和基因组学，下一代测序，统计遗传学，代谢生理学和流行病学方面拥有丰富的经验，并且具有长期有效的合作和领导记录，结合大量多种族，表型良好的样本，我们希望可以为RFA-DK-09-004做出贡献。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) shows complex inheritance, indicating a causal role for multiple inherited DNA variants. Genome wide association studies (GWAS) have now mapped over 20 novel loci where common variants are associated with risk of T2D. Despite this progress, identified risk alleles explain relatively little of the overall variation in T2D risk. To fully understand the genetic architecture of T2D we need to move from locus to gene to pinpoint specific causal gene(s) responsible for observed associations. We need to address allelic heteroaeneitv. where T2D genes are likely to have multiple different common and rare mutations. We need to explore ethnic variation, where the specific complement of gene mutations contributing to T2D are likely to vary in frequency and effect size across ethnic groups. We hypothesize that: (1) each region identified by GWAS contains at least one causal T2D gene, influenced by at least one common functional variant; (2) in addition to the index variant identified by GWAS, one or more additional common variants in each locus influence T2D; (3) in addition to common variants, each gene may harbor rare mutations that more strongly influence risk of T2D, and (4) the identities, frequencies and effects of these variants vary across multiple ethnic groups representative of the US population. To address these hypotheses we propose three Specific Aims. (1) Bring together multiethnic samples representative of the US population, drawn from the Jackson Heart Study, Framingham Heart Study, Multi-Ethnic Cohort Study, and Diabetes Prevention Program, that together include -29,000 individuals with T2D phenotypes and DNA; (2) Identify and fine-map common variants at each locus in each ethnic group by leveraging our multi-ethnic design and emerging data from the 1000 Genomes Project; and (3) Identify rare causal mutations at each locus by performing deep sequencing of all coding exons in each ethnic group. The co-investigators have extensive experience in complex disease genetics and genomics, next-generation sequencing, statistical genetics, metabolic physiology and epidemiology, and have a long track-record of effective collaboration and leadership that, combined with a large multiethnic, well-phenotyped sample, we hope can contribute to RFA-DK-09-004. RELEVANCE: Genetic studies of type 2 diabetes (T2D) have identified new genomic risk regions. We will look in these regions for genes, define variation within genes and variation in different people by bringing together -29,000 individuals from ethnic groups representing the US population, map genes in each region, and identify mutations by detailed DNA analysis, leading to better prevention and treatment of T2D.