Defining the genetic architecture of IBD in Ashkenazi Jewish populations

定义德系犹太人群体中 IBD 的遗传结构

• 批准号: 8688235
• 负责人: JUDY H. CHO
• 金额: $ 49.7万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688235
• 关键词: 19p13; 19q13; Accounting; Address; Affect; Alleles; American; Antigen-Antibody Complex; Architecture; Ashkenazim; Biological Assay; Case-Control Studies; Cells; Chromosomes; Crohn' s disease; Custom; Data; Data Set; Development; Disease; Disease Association; Disease model; Epidemiology; Etiology; European; Frequencies; Functional disorder; Gene Frequency; Genes; Genetic; Genetic Drift; Genome; Genotype; Haplotypes; Heritability; Immune; Inflammatory Bowel Diseases; Knowledge; Logistic Regressions; Major Histocompatibility Complex; Maps; Measures; Mediating; Medical; Modeling; Molecular; Morbidity - disease rate; Nature; Odds Ratio; Pathogenesis; Pattern; Play; Population; Predisposition; Prevalence; Recording of previous events; Recruitment Activity; Regression Analysis; Resolution; Risk; Role; Signal Transduction; TNF gene; Testing; Ulcerative Colitis; Variant; base; case control; cohort; exome; exome sequencing; follower of religion Jewish; genome sequencing; genome wide association study; improved; mortality; population based; response; risk variant; success

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.

描述（由申请人提供）：炎症性肠病（IBD）由克罗恩病和溃疡性结肠炎组成，影响约140万美国人。IBD流行病学的一个中心特征是德系犹太人的患病率增加了4.3-7.7倍。目前尚不清楚是什么因素导致了这种较高的发病率。本提案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）平台没有很好地检测到的较高效应的罕见变异导致了德系犹太人群体中的IBD。另一种假设是，在德系犹太人的积极选择，可能涉及一个功能网络的多个基因座，涉及共同的等位基因，显着贡献 与更高的患病率有关。提供了初步数据，详细说明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）犹太人和非犹太人欧洲祖先队列之间的群体亚结构的精确性质，c）德系犹太人克罗恩病的全基因组关联研究的结果，其证明了常见等位基因的很大程度上相似的遗传结构，d）犹太克罗恩病病例中的外显子组测序结果，证明存在Ashkenazim特有的不常见等位基因，e）目前参考序列在关键免疫调节区域如染色体19 p13上的KIR区域中的不足，f）在Th 17富集的细胞亚群中免疫介导的关联信号的富集，和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的罕见SNP来全面探索德系犹太人IBD患病率显著增加的潜在病因。在这方面，重要的是确定大型病例对照队列，为此建议增加招募。在德系犹太人中存在不常见的风险等位基因可能是由于遗传漂变，考虑到他们独特的人口历史。另一种可能性是，与非犹太欧洲血统队列相比，在多个基因座上的Ashkenazim作为功能模块的正选择增加了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确定义，并询问较弱的效应等位基因，将导致对已确定的易感性等位基因解释德系犹太人较高疾病患病率的程度进行总体估计（具体目标2）。与遗传性一样，这些估计值将提供一个关键的衡量标准，以评估确定疾病病理生理学的遗传因素的完整性。