Gene discoveries in subjects with Crohn's disease of African descent

描述（由申请人提供）：克罗恩病（CD）是一种高度遗传性疾病。全基因组关联研究（GWAS）已被证明在鉴定易感位点方面非常成功，其中许多位点定义了以前未被怀疑的在发病机制中起重要作用的途径。几乎所有的基因研究都集中在欧洲血统的高加索人身上，他们只占美国人口的70%。因此，这些遗传标记是否对混血儿有预测作用还有待观察，比如非洲裔美国人（AAs），他们占美国人口的15%，他们的每条染色体很可能是来自不同祖先群体的DNA块的马赛克。此外，来自HapMap和其他疾病研究的变异数据表明，AA人群中CD的等位基因结构可能与白种人有显著差异。对非裔美国人的研究仍然严重不足。因此，有必要通过招募大量的AA来扩大这些AA合并CD的基因发现研究，以增加样本量，提高发现的能力。在NIDDK IBDGC的辅助R01提案中，我们的目标是招募额外的1485名AA CD受试者，这些受试者可用于增加发现队列和IBDGC工作的复制研究。我们的目标是；目的1：非洲裔CD （AA）的详细表型特征。目标2：与IBDGC联合开展全基因组关联研究（GWAS），通过病例对照分析、通路分析和拷贝数变异（CNV）分析，发现非洲后裔（AA）的CD （IBD）基因/位点；目标3：通过对群体特异性SNP进行靶向测序，发现群体特异性SNP，然后对AA病例和对照组的常见SNP进行Illumina基因分型，完善全基因组关联峰。对欧洲血统的乳糜泻患者进行全基因组关联扫描，发现了40多种已证实的影响乳糜泻风险的变异。然而，悬而未决的问题是，在欧洲人身上发现的变异与AA人群的相关性如何？总之，我们对AA人群的高通量基因分型、最先进的分析和测序进行了强有力的研究，将发现、比较和对比欧洲人已经获得的CD知识。

DESCRIPTION (provided by applicant): Crohn's disease (CD) is a highly heritable disorder. Genome wide association studies (GWAS) have proved to be highly successful at identifying susceptibility loci, many of which define previously unsuspected pathways as playing an important role in pathogenesis. Nearly all genetic studies focused exclusively on Caucasians of European descent who represents only ~70% of the US population. Thus, it remains to be seen whether these genetic markers will have prognostic utility in admixed individuals, such as African Americans (AAs) who constitute about 15% of the US population and in whom each chromosome is likely to be a mosaic of blocks of DNA from different ancestral populations. Furthermore, variation data from the HapMap and other disease studies suggest the possibility that the allelic architecture of CD in AA populations may significantly differ from that in Caucasians. African American populations remain dramatically understudied. There is a great need to extend these gene discovery studies in AA with CD by recruiting a large numbers of AA to increase the sample size and to enhance the power of discovery. In this ancillary R01 proposal to NIDDK IBDGC, we aim to recruit additional 1485 AA CD subjects that can be used to augment the discovery cohort and for the replication studies to the IBDGC efforts. Our aims will be; Aim 1: Detailed phenotypic characterization of CD with African descent (AA). A minimum of 1000 AA subjects with CD will be recruited in 3 year period: Aim 2: Perform Genome Wide Association Study (GWAS) jointly with IBDGC to discover CD (IBD) genes / loci in CD with African descent (AA) using case control analysis, pathway analysis and CNV (copy number variation) analysis: Aim 3: Refine genome-wide association peaks by conducting targeted sequencing for population specific SNP discovery followed by Illumina genotyping of common SNPs in AA cases and controls. Genome-wide association scans in CD with European ancestry found more than 40 confirmed variants affecting the risk of developing CD. Open question, however, is how relevant the variants discovered in Europeans, are to AA population? Together, our well powered studies with high-throughput genotyping, state of the art analysis and sequencing in AA population with CD will discover, compare and contrast the already gained knowledge in Europeans in CD.