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Multiethnic Study of Type 2 Diabetes Genes

2 型糖尿病基因的多种族研究

基本信息

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
项目类别：
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

项目摘要

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）表现出复杂的遗传，表明多重遗传DNA的因果作用