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

摘要 克罗恩病（CD）是遗传性的。迄今为止，大多数基因发现都是在 欧洲血统的高加索人。非洲裔美国人（AAs）承受着与美国人类似的疾病负担。 高加索人，但不到1%的研究，出版物或临床试验集中在AA 的CD。这些遗传标记物是否对癌症有预后作用还有待观察。 混合个体，例如AA。此外，AA的患病风险更高 并发症，往往有更糟糕的疾病结果，这表明，潜在的生物学 AAs中的CD可能与高加索人不同。AA的基因组是混合的（约80%西 非洲人和20%高加索人），具有更大的多样性和更短的连锁不平衡（LD） 个街区.更高水平的多样性可以使遗传/后GWAS研究更具挑战性， 由于较短的物理LD区域，鉴定AA中的致病变体可能被证明更容易。我们 已经成功地完成了一个强大的GWAS基因发现AA。而普通 在高加索人中发现的易感性变异也通常在患有IBD的AA中发现， IBD、UC和人类白细胞抗原（HLA）区域中的AA特异性变体/基因座沿着 几个新的显著混合连锁不平衡区域和多种新信号 途径。根据这些令人兴奋的结果和发现，我们提出了一个后GWAS研究 全面识别非裔美国人中罕见的、因果性的和人群特异性的变异， 的CD。目标1：我们将通过额外招募和精细地图AA使AA队列规模增加一倍- 特异性和常见的（高加索人和AA）GWAS基因座，以检验假设， 由于AA中的LD较短，可以更容易地鉴定致病变体。目标2：测试 假设表达数量性状位点（eQTL）和基因网络分析将鉴定 新的AA特异性调控元件和致病基因座/罕见变体。目标3：全面执行 在AA病例中进行基因组测序（WGS）以发现罕见变异。我们提议， AA中的GWAS研究（如精细定位、eQTL和WGS）应与 高加索人，以加速IBD的基因和途径发现。将共同努力， 利用其现有资源与NIDDKGC合作开展。

ABSTRACT Crohn’s disease (CD) is heritable. Most genetic discovery to date has been performed in Caucasians of European descent. African Americans (AAs) endure a similar disease burden as Caucasians, yet less than 1% of research, publications, or clinical trials have focused on AA with CD. It remains to be seen whether these genetic markers will have prognostic utility in admixed individuals, such as AAs. Furthermore, AAs are at higher risk for disease complications and often have worse disease outcomes, suggesting that the underlying biology of CD in AAs may be different than Caucasians. The genome of AAs is admixed (~80% West African and 20% Caucasian), with greater diversity and shorter linkage disequilibrium (LD) blocks. Higher levels of diversity can make genetic / post-GWAS studies more challenging, but identifying causal variants in AA may prove easier because of shorter physical LD region. We have successfully completed a well-powered GWAS for gene discoveries in AA. While common susceptibility variants discovered in Caucasians are also generally found in AAs with IBD, new AA-specific variants/loci in IBD, UC and human leukocyte antigen (HLA) region along with several new regions of significant admixture linkage disequilibrium and multiple new signaling pathways. Following these exciting results and discoveries, we propose a post GWAS studies to comprehensively identify rare, causal and population specific variants in African Americans with CD. Aim 1: We will double our AA cohort size by additional recruitment and fine map AA- specific and common (to both Caucasians and AA) GWAS loci to test the hypothesis that causal variants can be identified more easily due to shorter LD among AAs. Aim 2: Test the hypothesis that expression quantitative trait loci (eQTL) and gene network analysis will identify new AA-specific regulatory elements and causal loci / rare variants. Aim 3: Perform whole genome sequencing (WGS) in AA cases for rare variant discovery. We propose that post GWAS studies such as fine mapping, eQTL, and WGS in AA should be conducted in parallel to Caucasians, to accelerate gene and pathway discovery in IBD. Proposed efforts will be jointly undertaken with NIDDKGC utilizing their available resources.