Defining the genetic architecture of IBD in Ashkenazi Jewish populations

描述(申请人提供)：炎症性肠病(IBD)由克罗恩病和溃疡性结肠炎组成，影响大约140万美国人。IBD流行病学的一个主要特征是，在德系犹太人人口中，疾病的流行率增加了4.3-7.7倍。目前尚不清楚是什么因素导致了这种较高的疾病患病率。这项提议将通过检验两个假设来解决这一差距。首先，我们假设，目前的全基因组关联研究(GWAS)平台没有很好地分析更高效应的罕见变异，这是导致德系犹太人IBD的原因。另一种假说是，在德系的正选择，可能涉及涉及共同等位基因的多个座位的功能网络，对 与较高的疾病患病率有关。提供的初步数据详细描述了a)IBD的遗传结构，在克罗恩病中独特地缺乏显性主要组织相容性复合体，b)犹太人和非犹太欧洲血统队列之间的人群亚结构的精确性质，c)在德系犹太人克罗恩病中的全基因组关联研究的结果，其证明了普通等位基因的基本相似的遗传结构，d)犹太克罗恩病病例的外显子组测序结果，证明了德系克隆氏病特有的不常见等位基因的存在，e)目前在关键免疫调节区(例如染色体19p13上的KIR区)中的参考序列的不足，F)在Th17丰富的细胞亚群中丰富免疫介导的关联信号，以及g)通过RNAseq实现的改进的分子分辨率。通过病例对照研究(具体目标1)，将通过询问外显子组和整个基因组中不常见的SNPs，全面探索在德意志联邦地区IBD患病率显著增加的根本病因。在这方面，重要的是确定大量病例控制队列，并提议为此增加征聘人员。考虑到其独特的种群历史，在德系祖人中存在不常见的危险等位基因可能是遗传漂移的结果。另一种可能性是，与非犹太欧洲血统队列相比，多个座位上的德系犹太人的阳性选择作为一个功能模块，增加了IBD的风险，并导致了更高的疾病患病率。通过回归分析和功能注释对相关等位基因进行精细的定义，再加上对影响较弱的等位基因进行询问，将综合估计已确定的易感等位基因在多大程度上导致了德什肯纳兹姆较高的疾病流行(具体目标2)。与遗传力一样，这些估计将提供一个关键衡量标准，用于评估已确定的遗传因素在定义疾病病理生理学方面的完整性。

DESCRIPTION (provided by applicant): The inflammatory bowel diseases (IBD) are comprised of Crohn's disease and ulcerative colitis and affect approximately 1.4 million Americans. A central feature of IBD epidemiology is the 4.3-7.7 fold increased prevalence of disease in Ashkenazi Jewish populations. It is unknown at present what factors account for this higher disease prevalence. This proposal will address this gap through testing two hypotheses. First, we hypothesize that uncommon variation of higher effects not well assayed by present genome-wide association study (GWAS) platforms contributes to IBD in Ashkenazi Jewish populations. An alternative hypothesis is that positive selection in the Ashkenazim, possibly involving a functional network of multiple loci involving common alleles, significantly contributes to the higher disease prevalence. Preliminary data are provided detailing a) the genetic architecture of IBD, with the unique absence of a dominant major histocompatibility complex in Crohn's disease, b) the precise nature of the population substructure between Jewish and non-Jewish European ancestry cohort, c) results of a genome-wide association study in Ashkenazi Jewish Crohn's disease which demonstrate a largely similar genetic architecture for common alleles, d) exome sequencing results in Jewish Crohn's disease cases, demonstrating the presence of uncommon alleles unique to the Ashkenazim, e) the present inadequacy of present reference sequences in critical immunoregulatory regions such as the KIR region on chromosome 19p13, f) enrichment of immune-mediated association signals in Th17-enriched cell subsets, and g) the improved molecular resolution achieved through RNASeq. A complete exploration of the underlying etiology for the markedly increased IBD prevalence in the Ashkenazim will be achieved through the interrogation of uncommon SNPs in the exome and throughout the genome through case control studies (Specific Aim 1). Important in this regard will be the ascertainment of large case-control cohorts, for which additional recruitment is proposed. The presence of uncommon risk alleles in the Ashkenazim might result from genetic drift, given their unique population history. An alternate possibility is that positive selection wthin the Ashkenazim at multiple loci, acting as a functional module, increases risk for IBD, and contributes to the higher disease prevalence compared to non-Jewish European ancestry cohorts. Refined definitions of associated alleles through regression analysis and functional annotation, together with interrogation of weaker effect alleles, will result in an aggregate estimate of the extent to which identified susceptibility alleles account for the higher disease prevalence in the Ashkenazim (Specific Aim 2). As with heritability, these estimates will provide a key measure of assessing the completeness of identified genetic factors in defining disease pathophysiology.