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: 8913947
• 负责人: JUDY H. CHO
• 金额: $ 49.41万
• 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/8913947
• 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 model; Epidemiology; Etiology; European; Frequencies; Functional disorder; Gene Frequency; Genes; Genetic; Genetic Drift; Genetic screening method; 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; Prevalence; Recording of previous events; Recruitment Activity; Regression Analysis; Resolution; Risk; Role; Signal Transduction; Susceptibility Gene; TNF gene; Testing; Ulcerative Colitis; Variant; 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流行病学的一个主要特征是4.3-7.7倍增加了Ashkenazi犹太人人群疾病的患病率。目前尚不清楚哪些因素涉及这种较高的疾病患病率。该建议将通过检验两个假设来解决这一差距。首先，我们假设，目前全基因组协会研究（GWAS）平台对较高效果的罕见变化对Ashkenazi犹太人群体的IBD有效。另一种假设是在Ashkenazim中的阳性选择，可能涉及一个涉及共同等位基因的多个基因座的功能网络，显着贡献了 疾病患病率较高。 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)外显子测序会导致犹太克罗恩病的病例，证明了Ashkenazim独有的不常见等位基因的存在，e）当前在关键免疫调节区域中当前参考序列不足之类rnaseq。通过对外显子组中不常见的SNP以及整个基因组通过病例控制研究的审查，将对Ashkenazim的IBD普遍存在显着增加的IBD患病率显着提高的基本病因进行完整探索（特定目标1）。在这方面，重要的是确定大病例对照人群，为此提出了其他招募。鉴于其独特的人口历史，在基氏菌中存在不常见的风险等位基因可能是遗传漂移所致。另一种可能性是，在多个基因座的Ashkenazim中，阳性选择充当功能模块，增加了IBD的风险，与非犹太欧洲血统同伙相比，疾病的患病率更高。通过回归分析和功能注释对相关等位基因的精致定义，以及较弱的效应等位基因的询问，将导致总估计确定的易感性等位基因在Ashkenazim中较高疾病患病率的程度（特定目标2）。与遗传力一样，这些估计将提供评估确定疾病病理生理学遗传因素完整性的关键衡量标准。