Beyond single-point GWAS: genetics of Crohn's disease in Ashkenazi Jews

描述（由申请人提供）：本申请涉及广泛的挑战领域（08）基因组学，超出GWAS 08-DK-102。克罗恩病（CD）等复杂疾病的整体遗传结构和致病机制目前还不完全清楚。全基因组关联研究（GWAS）已经确定了30多个与CD明确相关的遗传基因座。与CD相关的大量基因组位点仅占导致疾病的遗传变异的约20%。复杂疾病的一个基本挑战是试图确定这种“缺失的遗传性”的性质和来源。“复杂遗传学家面临的挑战是全面定义特定疾病的整体遗传结构。该建议超越了单点GWAS分析，通过GWAS数据的单倍型分析来识别导致疾病的不常见变异。我们建议利用克罗恩病遗传学中的主要遗传资源之一，即德系犹太人。在这一队列中观察到的显著较高的疾病患病率、家族相对风险和近亲结婚表明，在这里进行重点研究将特别富有成效。到目前为止，在主要非犹太欧洲血统GWAS中建立的关联信号并不能解释德系犹太人中观察到的较高疾病患病率，这表明应该尝试替代方法学方法，这构成了这项挑战补助金申请的基础。具体目标#1将对德系犹太人克罗恩病人群中鉴定的共享单倍型内的基因进行测序，以鉴定高致病性和保护性遗传变异。我们目前的数据表明，一个比预期的更大数量的不常见的单倍型区域，证明与克罗恩病在犹太人，但不是非犹太克罗恩病。对这些区域的基因进行测序可能会发现与克罗恩病相关的不常见变异。提出了一种利用共享单倍型队列和高通量测序的有效池化策略。具体目标#2将定义目标#1中确定的遗传变异在克罗恩病和溃疡性结肠炎的整体遗传结构中的作用。将通过犹太人和非犹太人病例对照队列的个体基因分型以及对构成相关单倍型的GWAS标志物进行基因分型来测试特定目标#1中鉴定的基于基因的变体，以确定这些不常见变体在克罗恩病的总体结构中的作用。 公共卫生相关性：克罗恩病是一种慢性肠道炎症，对整个基因组的基因扫描在识别与疾病相关的常见遗传变异方面非常成功。然而，一个主要的挑战是确定不太常见的变异，可能提供额外的洞察疾病的机制和潜在的治疗适用于选择受这些疾病影响的个体的子集。

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area (08) Genomics, Beyond GWAS 08-DK-102. The overall genetic architecture and pathogenic mechanisms of complex disorders such as Crohn's disease (CD) is incompletely defined at present. Genome-wide association studies (GWAS) have identified over 30 genetic loci that are definitively associated with CD. The large number of genomic loci which have been associated with CD only account for approximately 20% of the genetic variance contributing to disease. A fundamental challenge in complex disorders is attempting to determine the nature and sources of this "missing heritability." The resulting challenge for complex geneticists is to comprehensively define the overall genetic architecture of a particular disease. This proposal goes beyond single-point GWAS analyses to identify uncommon variation contributing to disease through haplotype analysis of GWAS data. We propose to leverage one of the major, genetic resources in Crohn's disease genetics, namely, the Ashkenazi Jewish population. The significantly higher disease prevalence, familial relative risk and endogamy observed in this cohort suggest that focused studies here would be particularly fruitful. The association signals thus far established in primarily non-Jewish European ancestry GWAS do not account for the higher disease prevalence observed among Ashkenazi Jews, suggesting that alternative methodologic approaches should be attempted, which forms the basis of this challenge grant application. Specific Aim #1 will sequence genes within shared haplotypes identified in Ashkenazi Jewish Crohn's disease populations in order to identify highly pathogenic and protective genetic variation. We present data demonstrating a greater than expected number of uncommon haplotype regions demonstrating association to Crohn's disease in Jewish, but not non-Jewish Crohn's disease. Sequencing of genes in these regions may identify uncommon variation associated with Crohn's disease. An efficient pooling strategy leveraging shared haplotype cohorts and high throughput sequencing is proposed. Specific Aim #2 will define the role of genetic variation identified in Aim #1 in the overall genetic architecture of Crohn's disease and ulcerative colitis. The gene- based variants identified in Specific Aim #1 will be tested through individual genotyping of Jewish and non-Jewish case-control cohorts, as well as genotype the GWAS markers that comprise the associated haplotype, to establish the role of these uncommon variants in the overall architecture of Crohn's disease. PUBLIC HEALTH RELEVANCE: Crohn's disease is a chronic inflammation of the intestines and genetic scans of the entire genome have been extremely successful in identifying common genetic variation that is associated with disease. However, a major challenge is to identify less common variation that may provide additional insight into disease mechanisms and potential therapies applicable to select subsets of individuals affected by these disorders.