Multiethnic Study of Type 2 Diabetes Genes

描述(由申请人提供)：2型糖尿病(T2D)显示复杂的遗传，表明多个遗传DNA变异的因果作用。全基因组关联研究目前已经定位了20多个新的基因座，其中常见的变异与T2D的风险相关。尽管取得了这一进展，但已识别的风险等位基因对T2D风险总体变化的解释相对较少。为了充分了解T2D的遗传结构，我们需要从一个基因座转移到另一个基因，以精确定位负责观察到的关联的特定原因基因(S)。我们需要解决等位基因异质性问题。其中T2D基因可能有多个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的特定基因突变互补在不同种族群体中的频率和影响大小可能不同。我们假设：(1)GWAS确定的每个区域至少包含一个因果T2D基因，受至少一个共同功能变量的影响；(2)除了GWAS确定的索引变量外，每个基因座上还有一个或多个额外的共同变量影响T2D；(3)除了共同变量外，每个基因可能包含罕见的突变，这些突变对T2D的风险产生更强烈的影响，以及(4)这些变量的身份、频率和效果在代表美国人口的多个种族群体中有所不同。为了解决这些假设，我们提出了三个具体目标。(1)收集代表美国人口的多种族样本，这些样本来自杰克逊心脏研究、弗雷明翰心脏研究、多种族队列研究和糖尿病预防计划，其中包括-29,000名具有T2D表型和DNA的个体；(2)利用我们的多种族设计和来自1000基因组计划的新兴数据，识别和精细绘制每个种族群体每个基因座的共同变异图谱；(3)通过对每个种族群体的所有编码外显子进行深度测序，确定每个基因座上罕见的因果突变。共同研究人员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，并拥有有效合作和领导的长期记录，结合大量多种族、表型良好的样本，我们希望能够为RFA-DK-09-004做出贡献。 相关性：2型糖尿病(T2D)的遗传学研究已经确定了新的基因组风险区域。我们将在这些区域寻找基因，通过汇集代表美国人口的29,000个种族群体的个人来定义基因内的变异和不同人的变异，绘制每个区域的基因图谱，并通过详细的DNA分析识别突变，从而更好地预防和治疗T2D。

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.