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

摘要 克罗恩病(CD)是可遗传的。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(AA)承受着类似的疾病负担 高加索人，然而只有不到1%的研究、出版物或临床试验专注于再生障碍性贫血 带CD。这些遗传标记是否有预后作用还有待观察。 混杂的个体，如AAs。此外，氨基酸患疾病的风险更高。 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Cd的含量可能与高加索人不同。AAS的基因组是混合的(~80%是West 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) 街区。更高水平的多样性可能会使遗传/后GWAS研究更具挑战性，但 识别再生障碍性贫血的因果变异可能更容易，因为物理LD区域较短。我们 已经成功地完成了在再生障碍性疾病中发现基因的强大的GWA。虽然很常见 在高加索人中发现的易感变异通常也在患有IBD的AA中发现，新的 IBD、UC和人类白细胞抗原(HL A)区的AA特异性变异/基因座 显著混合连锁不平衡和多个新信号的几个新区域 小路。在这些令人振奋的结果和发现之后，我们提出了一项后GWAS研究 全面识别非洲裔美国人中罕见的、因果的和特定于人群的变异 带CD。目标1：我们将通过增加招募和精细地图AA- (对高加索人和再生障碍者都是)特定和常见的GWA基因座，以检验这一假设 由于AA之间的LD较短，因此可以更容易地识别因果变异。目标2：测试 假设表达数量性状基因座(EQTL)和基因网络分析将识别 新的AA特异性调控元件和因果基因座/稀有变异。目标3：整体执行 再生障碍性贫血病例的基因组测序(WGS)以发现罕见的变异。我们提议这一职位 在AA中进行精细定位、eQTL和WGS等GWAS研究应与 高加索人，以加速IBD的基因和途径发现。拟议的努力将联合 与NIDDKGC利用其现有资源进行合作。

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.