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

描述(申请人提供)：炎症性肠病，影响140万美国人，以慢性肠道炎症为特征，包括两个主要亚型，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。德系犹太人的克隆氏病患病率是其他欧洲血统人口的4.3到7.7倍。最近对克罗恩病进行的一项特定于德系克隆氏病的全基因组关联研究的结果显示，在一个普通的欧洲血统队列中，与先前建立的关联信号显著重叠，这表明高频疾病相关变异的遗传结构相似。然而，相关基因座的综合影响在德系犹太人中占遗传率的比例比在非犹太队列中要小，这导致我们假设，德系犹太人人群中克罗恩病患病率增加的遗传病因主要是由中或大效应的罕见变异驱动的，到目前为止，全基因组关联扫描对这些变异的分析很差。具体目标：研究提案包括三个具体目标。第一个目标将结合我们之前的德系克隆氏病患者特异性关联研究的数据和来自德系克隆氏病患者外显子组测序的新数据，以测试病例对照关联的新变种。我们还将使用生物信息学和统计分析来选择新发现的变异的一个子集，用于在一个大型的德系病例对照队列中进行后续基因分型。第二个目标将评估和修改稀有功能变异的统计关联分析方法，并将应用这些策略来优化来自目标1的德系犹太人基因数据集中新关联信号的检测。为了估计变异的功能影响，该分析将整合多种外部数据来源，包括自然选择的特征、进化保护、生物网络以及转录和氨基酸编码中的修改。我们的第三个目标将利用全基因组测序数据来改进单倍型和完善遗传进化史。这将把以疾病为导向的分析从目标2扩展到包括复合杂合性和每个变异的分子进化。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：该项目不仅将有助于揭示德系犹太人克隆氏病的分子病因学，还将潜在地阐明导致所有患者疾病发病的分子机制和途径。这可能有助于为开发新的治疗方法确定新的目标，这些新方法将对所有祖先的克罗恩病患者有效。

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.