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

描述（由申请人提供）：炎症性肠病以慢性肠道炎症为特征，包括克罗恩病和溃疡性结肠炎两种主要亚型，影响140万美国人。遗传因素对该病的遗传性和发病机制至关重要。德系犹太人的克罗恩病患病率是其他欧洲血统人群的4.3到7.7倍。最近一项针对德系犹太人的克罗恩病全基因组关联研究发现，与先前在一般欧洲血统队列中建立的关联信号有显著重叠，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率比在非犹太人群中要小，这使我们假设德系犹太人中克罗恩病患病率增加的遗传病因学主要是由中等或较大影响的罕见变异驱动的，迄今为止，全基因组关联扫描对这种变异的分析很差。具体目标：研究计划包括三个具体目标。第一个目标将结合我们之前德系犹太人特异性关联研究的数据和德系犹太人克罗恩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异。我们还将使用生物信息学和统计学分析来选择一个新发现的变异子集，用于在一个大型德系犹太人病例对照队列中进行后续基因分型。第二个目标是评估和修改分析罕见功能变异统计关联的方法，并将这些策略应用于优化检测来自aim 1的德系犹太人基因型数据集中的新关联信号。为了评估变异的功能影响，该分析将整合多种外部数据来源，包括自然选择、进化保护、生物网络、转录和氨基酸编码的修饰等特征。我们的第三个目标是利用全基因组测序数据来改进单倍型和完善遗传进化史。这将从Aim 2扩展到以疾病为导向的分析，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，因此这三个目标的进展将同时进行。

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.