Rare Variants and Risk of Type 1 Diabetes

1 型糖尿病的罕见变异和风险

• 批准号: 8668054
• 负责人: Stephen S. Rich
• 金额: $ 66.81万
• 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/8668054
• 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; rare 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，是由多种遗传和环境风险因素的作用引起的，并且可能影响300名儿童中有1个。 2001年，建立了1型糖尿病遗传联盟（T1DGC）的目标，其目标是进行大规模的遗传研究，以识别基因组中有助于T1D风险的区域，并为更广泛的科学社区提供了组装的数据和生物测量。 T1DGC使用（a）候选基因，（b）MHC中的变体，（c）全基因组链接和（d）全基因组全基因组关联扫描（GWAS）进行了T1D的最强大的T1D研究。从我们对超过16,000例病例和对照组的GWAS荟萃分析中，有18个新鉴定的基因座的基因组显着性（P D 5 x 10-8），包括4,267例独立的4,267例，4,463例控制和2,319个家庭中的复制证据。这使T1D基因座的总数达到了42。我们现在已经进行了新型18个基因座的后续基因分型，并在所有已知的T1D基因座中进行了密集的SNP映射（使用免疫芯片）。我们在大多数基因座中发现了一个T1D候选基因。通过分析常见遗传变异发现的GWAS的基因座解释了T1D总遗传负债的15％（在MHC中由基因贡献了50％之后）。残留的遗传风险（“缺乏遗传力”）可能是由于基因编码区域中发现的罕见变异。这些罕见的编码变体可能会起作用，对风险有很大影响。与共同的变体不同，这些编码和调节区域的DNA测序是发现罕见功能变体所必需的。即使是编码区域（“外来”）的测序工作，也以巨大的代价进行。对于T1D与稀有变体的测试关联，基因分型阵列（外观）是由12,000多个人类外来设计设计的。该自定义阵列将通过以降低的成本进行大量样品来测试稀有变体。 Exomehip包含约200,000个非同义词，非sense和剪接站点的变体，以及100,000个变体，用于附加内容（包括MHC变体）。该赠款应用的主要目的是发现新的遗传风险因素，这些遗传风险因素有助于T1D的风险1）在2500 T1DGC受影响的SIB对（ASP）家族的良好表征集合中进行外部基因分型； 2）对EXOMECHIP数据进行分析（单个SNP和负担测试），以发现其功能意义上的变体影响T1D风险的新基因； 3）通过在约7,000个T1D病例和约7,000个对照中进行靶向测序来复制这些新的结果。我们将整合现有数据（HLA键入，免疫光，CNV，Exomehip），以对与T1D风险相关的稀有，常见和结构变化进行全面分析。这些发现应导致病因学和T1D预测，预防和治疗的新途径。