Multiethnic Study of Type 2 Diabetes Genes

2 型糖尿病基因的多种族研究

• 批准号: 8131994
• 负责人: David Altshuler
• 金额: $ 220万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131994
• 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（T2 D）显示复杂的遗传，表明多重遗传DNA的因果作用 变体。全基因组关联研究（GWAS）现已绘制了20多个新的基因座， 变异与T2 D风险相关。尽管取得了这一进展，但已确定的风险等位基因解释的相对较少。 T2 D风险的总体变化。为了充分了解T2 D的遗传结构，我们需要从 基因座到基因，以查明负责观察到的关联的特定因果基因。我们需要解决 等位异基因其中T2 D基因可能具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T2 D的基因突变的特定互补是 可能在不同种族群体中的频率和效应大小不同。我们假设：（1）每个区域 GWAS鉴定的T2 D基因至少包含一个致病T2 D基因，受至少一个共同功能基因的影响， （2）除了GWAS识别的索引变体之外， 每个基因座都影响T2 D;（3）除了常见的变异，每个基因可能含有罕见的突变， 更强烈地影响T2 D的风险，以及（4）这些变体的特性、频率和影响不同 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，来自 杰克逊心脏研究、心脏病研究、多种族队列研究和糖尿病预防 程序，其一起包括约29，000个具有T2 D表型和DNA的个体;（2）识别和精细映射 通过利用我们的多种族设计， 来自1000个基因组计划的数据;以及（3）通过执行以下操作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。合作研究者有着丰富的经验 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，并有长期的有效合作和领导记录， 结合大量多种族、表型良好的样本，我们希望能够为RFA-DK-09-004做出贡献。 相关性（参见说明）： 2型糖尿病（T2 D）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 基因区域，通过将-29，000个基因集合在一起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，并确定 通过详细的DNA分析，可以更好地预防和治疗T2 D。