Multiethnic Study of Type 2 Diabetes Genes

2 型糖尿病基因的多种族研究

• 批准号: 8321606
• 负责人: David Altshuler
• 金额: $ 234.34万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321606
• 关键词: Address; African American; Alleles; American; Architecture; Asian Americans; Biological; Cell physiology; Chromosome Mapping; Clinical Data; Code; Cohort Studies; Collaborations; Collection; Communities; Complement; Complex; DNA; DNA analysis; Data; Epidemiology; Ethnic group; Exons; Framingham Heart Study; Frequencies; Gene Mutation; Genes; Genetic; Genetic Research; Genome; Genomics; Genotype; Hawaiian population; Heart; Hereditary Disease; Human; Individual; Inherited; Instruction; Insulin Resistance; Intervention; Latino; Leadership; Life Style; Linkage Disequilibrium; Maps; Metabolic; Mutation; Native Americans; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Participant; Phenotype; Physiology; Population; Population Genetics; Prevention; Principal Investigator; Property; Protocols documentation; Randomized Clinical Trials; Research Design; Research Personnel; Resources; Risk; Role; Sampling; Signal Transduction; United States; Variant; cohort; density; design; diabetes mellitus genetics; diabetes prevention program; diabetes risk; experience; follow-up; genetic variant; genome wide association study; genome-wide; improved; indexing; next generation; novel; population based; trait

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 (See instructions): 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.

2 型糖尿病 (T2D) 显示出复杂的遗传，表明多重遗传 DNA 具有因果作用 变种。全基因组关联研究 (GWAS) 现已绘制了 20 多个常见的新位点 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以下问题的解释相对较少： T2D 风险的总体变化。为了充分了解 T2D 的遗传结构，我们需要从 基因座以查明负责观察到的关联的特定因果基因。我们需要解决 等位基因异质性。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 的基因突变的特定互补是 不同种族群体的频率和影响大小可能有所不同。我们假设：（1）每个区域 经 GWAS 鉴定，包含至少一种致病性 T2D 基因，并受到至少一种常见功能的影响 变体； (2) 除GWAS鉴定的指标变异外，还需要添加一种或多种常见变异 每个位点影响 T2D； (3) 除了常见的变异之外，每个基因还可能含有罕见的突变， 更强烈地影响 T2D 风险，并且 (4) 这些变异的特性、频率和影响各不相同 跨越代表美国人口的多个种族群体。为了解决这些假设，我们提出 三个具体目标。 (1) 汇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、弗雷明汉心脏研究、多种族队列研究和糖尿病预防 计划，总共包括 -29,000 名具有 T2D 表型和 DNA 的个体； (2) 识别和精细定位 通过利用我们的多种族设计和新兴技术，在每个种族群体的每个基因座上发现常见变异 来自千人基因组计划的数据； (3) 通过执行来识别每个位点的罕见因果突变 对每个种族的所有编码外显子进行深度测序。共同研究者拥有丰富的经验 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，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，我们希望能为 RFA-DK-09-004 做出贡献。 相关性（参见说明）： 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。我们将看看这些 基因区域，通过汇集 -29,000 来定义基因内的变异和不同人的变异 来自代表美国人口的种族群体的个体，绘制每个地区的基因图谱，并识别 通过详细的 DNA 分析进行突变，从而更好地预防和治疗 T2D。