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）已被证明是非常成功的，在确定易感基因座，其中许多定义以前未被怀疑的途径在发病机制中发挥重要作用。几乎所有的遗传学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，这些遗传标记在混合个体中是否具有预后效用还有待观察，例如非洲裔美国人（AAs）占美国人口的约15%，并且其中每条染色体可能是来自不同祖先群体的DNA块的镶嵌。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高加索人显著不同。非洲裔美国人的研究仍然严重不足。有一个很大的需要，以扩大这些基因发现研究在AA与CD招募大量的AA，以增加样本量，提高权力的发现。在NIDDK IBDGC的辅助R 01提案中，我们的目标是招募额外的1485例AA CD受试者，可用于扩大发现队列和IBDGC的复制研究。我们的目标将是：目标1：详细的CD与非洲血统（AA）的表型特征。3年内将招募至少1000例患有CD的AA受试者：目的2：与IBDGC联合进行全基因组关联研究（GWAS），使用病例对照分析、途径分析和CNV发现患有CD的非洲裔（AA）中的CD（IBD）基因/位点（拷贝数变异）分析：目的3：优化基因组-通过对群体特异性SNP发现进行靶向测序，然后对AA病例中的常见SNP进行Illumina基因分型，对照在CD与欧洲血统的全基因组关联扫描中，发现了40多种影响CD发展风险的确认变异。然而，悬而未决的问题是，在欧洲人中发现的变异与AA人群有多大关系？总之，我们在患有CD的AA人群中进行的高通量基因分型、最先进分析和测序的有力研究将发现、比较和对比欧洲人在CD方面已经获得的知识。

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.