Rare Variants and Risk of Type 1 Diabetes

1 型糖尿病的罕见变异和风险

• 批准号: 8497685
• 负责人: Stephen S. Rich
• 金额: $ 48.74万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497685
• 关键词: Accounting; Address; Affect; Alleles; Applications Grants; Autoimmune Diseases; Candidate Disease Gene; Child; Code; Collection; Communities; Complex; Custom; DNA Sequence; Data; Environmental Risk Factor; Etiology; Family; Genes; Genetic; Genetic Risk; Genome; Genomics; Genotype; Goals; Haplotypes; Heritability; Human; Indium; Individual; Insulin-Dependent Diabetes Mellitus; Lead; Mediating; Meta-Analysis; Mining; National Heart, Lung, and Blood Institute; Nucleic Acid Regulatory Sequences; Participant; Pathway interactions; Phenotype; Population Genetics; Prevention therapy; RNA Splicing; Reporting; Request for Applications; Research; Research Design; Residual state; Risk; Role; Sample Size; Sampling; Scanning; Single Nucleotide Polymorphism Map; Site; Structure of beta Cell of islet; Susceptibility Gene; Technology; Testing; Translating; Variant; base; case control; cost; design; diabetes mellitus genetics; diabetes risk; disorder risk; exome; exome sequencing; follow-up; gene discovery; genetic risk factor; genetic variant; genome wide association study; genome-wide; genome-wide linkage; human leukocyte antigen gene; insight; knowledge base; loss of function; non-genetic; novel; risk variant; success; theories

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is a complex autoimmune disorder that arises from the action of multiple genetic and environmental risk factors and can affect up to 1 in 300 children. In 2001, the Type 1 Diabetes Genetics Consortium (T1DGC) was established with the goals of conducting large-scale genetic studies to identify regions in the genome that contribute to T1D risk and making available the assembled data and biospecimens to the broader scientific community. The T1DGC has been highly successful conducting the most robustly powered studies of T1D using (a) candidate genes, (b) variants in the MHC, (c) genome-wide linkage, and (d) genome-wide association scan (GWAS). From our GWAS meta-analysis of over 16,000 cases and controls, 18 newly identified loci were reported at genome-wide significance (P d 5 x 10-8), including replication evidence in an independent set of 4,267 cases, 4,463 controls and 2,319 families. This brought the total number of T1D loci to 42. We have now conducted follow-up genotyping of the novel 18 loci, and conducted dense SNP mapping (using the ImmunoChip) in all known T1D loci. We have discovered a single T1D candidate gene in the majority of these loci. The loci from GWAS discovered through analysis of common genetic variants explain less than 15% of the total genetic liability of T1D (after the 50% contributed by genes in the MHC). The residual genetic risk ("missing heritability") may be due to rare variants that are found in coding regions of genes. These rare coding variants are likely to be functional with large effects on risk. Unlike common variants, DNA sequencing of these coding and regulatory regions is required for discovery of rare functional variants. The sequencing effort, even of the coding regions (the "exome") is performed at significant cost. For testing association of T1D with rare variants, a genotyping array (the ExomeChip) has been designed from over 12,000 human exomes. This custom array will permit testing of rare variants by genotyping large numbers of samples at reduced cost. The ExomeChip contains ~200,000 non-synonymous, non-sense, and splice-site variants, as well as 100,000 variants for additional content (including MHC variants). The primary aims of this grant application are to discover novel genetic risk factors that contribute to risk of T1D by 1) conducting ExomeChip genotyping in a well-characterized collection of 2,500 T1DGC affected sib pair (ASP) families; 2) performing analyses of the ExomeChip data (both single SNP and burden tests) in order to discover new genes whose functionally significant variants influence risk to T1D; and 3) replicating these novel results by targeted sequencing in ~7,000 T1D cases and ~7,000 controls. We will integrate existing data (HLA typing, ImmunoChip, CNV, ExomeChip) to provide a comprehensive analysis of rare, common, and structural variation associated with T1D risk. These findings should lead to novel pathways of etiology and avenues for T1D prediction, prevention and therapy.

描述（由申请人提供）：1 型糖尿病 (T1D) 是一种复杂的自身免疫性疾病，由多种遗传和环境风险因素的作用引起，可影响多达三百分之一的儿童。 2001 年，1 型糖尿病遗传学联盟 (T1DGC) 成立，其目标是进行大规模遗传学研究，以确定基因组中导致 T1D 风险的区域，并向更广泛的科学界提供收集的数据和生物样本。 T1DGC 使用 (a) 候选基因、(b) MHC 变异、(c) 全基因组连锁和 (d) 全基因组关联扫描 (GWAS) 成功地开展了最有力的 T1D 研究。根据我们对 16,000 多个病例和对照的 GWAS 荟萃分析，报告了 18 个新发现的基因座，具有全基因组显着性 (P d 5 x 10-8)，包括一组独立的 4,267 个病例、4,463 个对照和 2,319 个家庭的复制证据。这使得 T1D 位点总数达到 42 个。我们现在已经对新的 18 个位点进行了后续基因分型，并在所有已知的 T1D 位点中进行了密集 SNP 作图（使用免疫芯片）。我们在这些基因座的大多数中发现了一个 T1D 候选基因。通过对常见遗传变异的分析发现的 GWAS 位点解释了 T1D 总遗传责任的不到 15%（在 MHC 中的基因贡献了 50% 之后）。残余遗传风险（“遗传性缺失”）可能是由于基因编码区域中发现的罕见变异造成的。这些罕见的编码变体很可能发挥作用，对风险产生巨大影响。与常见变异不同，发现罕见功能变异需要对这些编码区和调控区进行 DNA 测序。测序工作，甚至是编码区（“外显子组”）的测序工作，其成本都很高。为了测试 T1D 与罕见变异的关联，我们根据 12,000 多个人类外显子组设计了基因分型芯片（ExomeChip）。这种定制阵列将允许通过以较低的成本对大量样本进行基因分型来测试罕见变异。 ExomeChip 包含约 200,000 个非同义、无义和剪接位点变体，以及 100,000 个附加内容变体（包括 MHC 变体）。本拨款申请的主要目的是通过以下方式发现导致 T1D 风险的新遗传风险因素：1) 在 2,500 个受 T1DGC 影响的同胞对 (ASP) 家庭的特征良好的集合中进行 ExomeChip 基因分型； 2) 对 ExomeChip 数据进行分析（单一 SNP 和负荷测试），以发现其功能上显着变异影响 T1D 风险的新基因； 3) 通过靶向测序在约 7,000 例 T1D 病例和约 7,000 例对照中复制这些新结果。我们将整合现有数据（HLA 分型、免疫芯片、CNV、外显子组芯片），对与 T1D 风险相关的罕见、常见和结构变异进行全面分析。这些发现将为 T1D 预测、预防和治疗带来新的病因学途径和途径。