Replication of Association Signals Identified in Ulcerative Colitis GWAS

溃疡性结肠炎 GWAS 中鉴定的关联信号的复制

• 批准号: 8102577
• 负责人: Richard H Duerr
• 金额: $ 20万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-23 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102577
• 关键词: 12q15; 1p36; Abbreviations; Ankylosing spondylitis; Applications Grants; Austria; Biological Assay; Budgets; Characteristics; Chromosomes; Chronic; Clinical; Crohn' s disease; Data; Data Coordinating Center; Data Set; Development; Disease; Enterobacteriaceae; Environment; European; Gender; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genomics; Genotype; Germany; Goals; Health; Immune; Individual; Inflammatory Bowel Diseases; International; Italy; Laboratories; Lead; Major Histocompatibility Complex; Maps; Mediating; Meta-Analysis; Mucosal Immune Responses; National Institute of Diabetes and Digestive and Kidney Diseases; Netherlands; North America; Pathogenesis; Polymerase Chain Reaction; Population Control; Principal Investigator; Proteomics; Psoriasis; Quality Control; Research Personnel; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Structure; Time; Ulcerative Colitis; Variant; case control; cost; follow-up; genome wide association study; genome-wide; genotyping technology; improved; response; thyroid associated ophthalmopathies

DESCRIPTION (provided by applicant): The overall goal of this application is to discover genetic risk loci for ulcerative colitis by attempting to replicate/extend the evidence for association at single nucleotide polymorphisms (SNPs) identified in a metaanalysis of ulcerative colitis genome-wide association studies (GWAS). Ulcerative colitis and Crohn's disease are the two major forms of inflammatory bowel disease. They are thought to result from a dysregulated mucosal immune response triggered by ubiquitous enteric bacteria in genetically susceptible individuals. The two disorders share many characteristics but unique clinical features also distinguish them, suggesting that they share some genetic susceptibility loci but differ at others. Genome-wide significant evidence for 32 Crohn's disease loci was found in a GWAS meta-analysis and replication study. Variants in IL23R and the major histocompatibility complex are associated with both ulcerative colitis and Crohn's disease, but most of the identified Crohn's disease loci show only nominal or no significant evidence for association with ulcerative colitis. The NIDDK Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC) recently completed an ulcerative colitis GWAS using Illumina genotyping beadchip data from 977 cases and 2,122 controls that passed quality control and were matched, by gender and ancestry. The NIDDK IBDGC's ulcerative colitis GWAS and a limited replication study in additional case-control samples, all of European ancestry, identified ulcerative colitis loci on chromosomes 1p36 and 12q15, in addition to IL23R and the major histocompatibility complex. A meta-analysis of the NIDDK IBDGC and two additional ulcerative colitis GWAS datasets, all generated in European ancestry case-control samples using Illumina genotyping beadchips, is underway. The ulcerative colitis GWAS meta-analysis is expected to include post quality control data for approximately 280,000 SNPs in more than 2,600 cases and approximately twice this number of controls. This grant application proposes to attempt to replicate/extend the most promising ulcerative colitis GWAS meta-analysis association signals in additional European ancestry case-control samples from North America, the Netherlands, Germany, Austria and Italy. In addition to genotyping the replication samples at SNPs with promising association evidence in the ulcerative colitis GWAS meta-analysis, ancestry informative markers will also be genotyped so that association analyses can be controlled for population structure. Genotyping technologies and costs are constantly evolving, so it is difficult to predict which genotyping platform will be most cost-effective, how many replication samples can be genotyped, how deep into the ulcerative colitis GWAS meta-analysis hit list the replication analyses can go, and how many ancestry informative markers can be genotyped within budget limitations at the time the proposed study would commence. The tentative plan is to use a 768-plex Illumina GoldenGate assay to genotype more than 500 of the top ulcerative colitis metaanalysis hits plus a set of SNPs that discern ancestry strata within European ancestry samples.

描述（由申请人提供）：本申请的总体目标是通过试图在单核苷酸多态性（SNP）（SNP）进行溃疡性结肠炎基因组基因组基因组基因组基因组基因组关联研究（GWAS）中发现的单核苷酸多态性（SNP）的相关证据来发现溃疡性结肠炎的遗传风险基因座。溃疡性结肠炎和克罗恩病是炎症性肠病的两种主要形式。人们认为它们是由遗传易感个体无处不在的肠细菌引起的粘膜免疫反应失调引起的。这两种疾病具有许多特征，但独特的临床特征也将它们区分开来，这表明它们具有某些遗传敏感性基因座，但在其他方面有所不同。在GWAS荟萃分析和复制研究中发现了全基因组的32个克罗恩病基因座的重要证据。 IL23R和主要的组织相容性复合物中的变体与溃疡性结肠炎和克罗恩病有关，但是大多数确定的克罗恩病基因座基因座仅显示出称为或没有显着证据表明与溃疡性结肠炎相关的证据。 NIDDK炎症性肠病遗传学联盟（NIDDK IBDGC）最近使用来自977例病例的Illumina Genotimina Genotyping Beadchip数据完成了溃疡性结肠炎，并通过质量控制，并通过性别和祖先匹配了通过质量控制的2,122个对照。 NIDDK IBDGC的溃疡性结肠炎GWA和在其他病例对照样本中进行的有限复制研究，所有欧洲血统，除了IL23R以及主要的组织相容性复合物外，还确定了染色体1p36和12q15染色体上的溃疡性结肠炎基因座。 NIDDK IBDGC的荟萃分析和两个额外的溃疡性结肠炎GWAS数据集，所有这些数据集都在欧洲血统的病例对照样品中使用Illumina Genotimina Genotyping Beadchips产生。溃疡性结肠炎GWAS荟萃分析预计将包括2,600多例病例的大约280,000个SNP的质量控制数据，并将大约两倍的对照组。该赠款申请提议在来自北美，荷兰，德国，奥地利和意大利的其他欧洲血统案例对照样本中，试图在欧洲血统案例对照样本中复制/扩展最有前途的溃疡性结肠炎GWAS元分析协会信号。除了在溃疡性结肠炎GWAS荟萃分析中具有有前途的关联证据的SNP的重复样本外，还将对祖先提供信息标记物进行基因分型，以便可以控制关​​联分析的人口结构。基因分型技术和成本正在不断发展，因此很难预测哪种基因分型平台将是最具成本效益的，可以进行基因分型的多少复制样本，对溃疡性结肠炎gwas荟萃分析的深入访问列表，复制分析可以进行，以及在预算范围内进行预算的限制。暂定计划是使用768个质子光明测定法对超过500个顶级溃疡性结肠炎荟萃分析的命中以及一组SNP，这些SNP识别欧洲血统样本中的祖先地层。