The genetics of Crohn's disease in the Ashkenazi Jewish population

德系犹太人克罗恩病的遗传学

• 批准号: 8626173
• 负责人: KEN HUI
• 金额: $ 4.77万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626173
• 关键词: Accounting; Affect; American; Amino Acids; Architecture; Ashkenazim; Bioinformatics; Biological; Biological Assay; Cataloging; Catalogs; Chronic; Code; Collection; Crohn' s disease; Data; Data Set; Data Sources; Detection; Development; Disease; Disease Association; Ethnic Origin; Etiology; European; Exhibits; Experimental Designs; Frequencies; Functional RNA; Gene Frequency; Gene Mutation; General Population; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Structures; Genetic Transcription; Genome; Genomics; Genotype; Haplotypes; Heritability; High-Throughput Nucleotide Sequencing; Immunologics; Individual; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Medical; Methods; Modification; Molecular; Molecular Evolution; Morbidity - disease rate; Mutation; Natural Selections; Nature; Open Reading Frames; Pathogenesis; Pathway interactions; Patients; Phase; Play; Population; Population Genetics; Population Sizes; Prevalence; Process; Proteins; Recording of previous events; Research Proposals; Role; Sampling; Signal Transduction; Source; Technology; Testing; Ulcerative Colitis; Variant; Work; base; case control; cohort; density; disease-causing mutation; exome; exome sequencing; follow-up; follower of religion Jewish; genetic analysis; genetic variant; genome sequencing; genome wide association study; genome-wide; improved; insight; mortality; new therapeutic target; novel; public health relevance; rare variant; screening; success

DESCRIPTION (provided by applicant): Inflammatory bowel disease, which affects 1.4 million Americans, is characterized by chronic intestinal inflammation and comprises two major subtypes, Crohn's disease and ulcerative colitis. Genetic factors are central to the heritability and pathogenesis of this disease. The Ashkenazi Jewish population exhibits a population prevalence of Crohn's disease that is 4.3 to 7.7-fold greater than in other European- ancestry populations. Findings from a recent Ashkenazi-specific genome-wide association study of Crohn's disease showed significant overlap with previously established association signals in a general European- ancestry cohort, suggesting a similar genetic structure for high-frequency disease-related variation. The combined effect of the associated loci, however, accounted for a proportion of heritability that was smaller in the Ashkenazim than in the non-Jewish cohort, leading us to hypothesize that the genetic etiology of the increased Crohn's disease prevalence in the Ashkenazi Jewish population is primarily driven by rare variants of moderate or large effect, which have to date been poorly assayed by genome-wide association scans. Specific aims: The research proposal comprises three specific aims. The first aim will combine data from our previous Ashkenazi-specific association study and new data from exome sequencing of Ashkenazi Crohn's disease patients in order to test novel variants for case-control association. We will also use bioinformatic and statistical analyses to select a subset of newly discovered variants for follow-up genotyping in a large Ashkenazi case-control cohort. The second aim will evaluate and modify methods for analyzing statistical association of rare functional variants and will apply these strategies to optimize the detection of novel association signals in the Ashkenazi Jewish genotype datasets from Aim 1. To estimate variants' functional impacts, this analysis will integrate multiple outside sources of data, including signatures of natural selection evolutionary conservation, biological networks, and modifications in transcription and amino acid coding. Our third aim will utilize whole-genome sequencing data to improve haplotyping and refine genetic evolutionary history. This will extend the disease-oriented analysis from Aim 2 to include compound heterozygosity and the molecular evolution of each variant. Since each aim employs a different dataset, progress on all three aims will be made concurrently. Public health relevance: This project will not only help uncover the molecular etiology of Crohn's disease in the Ashkenazi Jewish population, but will potentially elucidate molecular mechanisms and pathways that generally contribute to disease pathogenesis in all patients. This may help to define new targets for the development of new treatments that will be effective for Crohn's disease patients of all ancestries.

描述（由申请人提供）：炎症性肠病影响140万美国人，其特征在于慢性肠道炎症，包括两种主要亚型，克罗恩病和溃疡性结肠炎。遗传因素是这种疾病的遗传性和发病机制的核心。德系犹太人群体表现出克罗恩病的群体患病率是其他欧洲血统群体的4.3至7.7倍。最近一项针对克罗恩病的德系犹太人特异性全基因组关联研究的结果显示，与先前在一般欧洲血统队列中建立的关联信号存在显著重叠，表明高频疾病相关变异的遗传结构相似。然而，相关基因座的综合效应在德系犹太人中所占的遗传力比例小于非犹太人群体，这使我们假设德系犹太人克罗恩病患病率增加的遗传病因主要是由罕见的中度或重度效应变体驱动的，迄今为止，全基因组关联扫描对这些变体的检测结果很差。具体目标：研究提案包括三个具体目标。第一个目标将结合联合收割机的数据，从我们以前的德系特异性关联研究和新的数据，从外显子组测序的德系克罗恩病患者，以测试新的变异的病例对照关联。我们还将使用生物信息学和统计分析来选择一个新发现的变异子集，用于大型德系犹太人病例对照队列的后续基因分型。第二个目标将评估和修改用于分析罕见功能变体的统计关联的方法，并将这些策略应用于优化Aim 1的德系犹太人基因型数据集中新关联信号的检测。为了估计变异的功能影响，该分析将整合多个外部数据源，包括自然选择进化保护，生物网络以及转录和氨基酸编码的修饰。我们的第三个目标是利用全基因组测序数据来改进单体型分析和完善遗传进化史。这将扩展目标2的疾病导向分析，以包括复合杂合性和每个变体的分子进化。由于每个目标使用不同的数据集，因此将同时在所有三个目标上取得进展。公共卫生相关性：该项目不仅有助于揭示德系犹太人克罗恩病的分子病因，而且可能阐明通常导致所有患者发病的分子机制和途径。这可能有助于确定新的治疗目标，以开发对所有血统的克罗恩病患者都有效的新治疗方法。