IBD Gene Mapping by Clinical and Population Subset

项目摘要炎症性肠病(IBD)、克罗恩病(CD)和溃疡性结肠炎(UC)是 复杂的胃肠道遗传性疾病，是患者和社会的主要健康负担。 在IBD遗传病因学的解剖方面取得了巨大进展，已发现200多个IBD基因座 通过全基因组联合研究(GWAS)，但主要限于欧洲血统的人。IBD 遗传学联合会(IBDGC)的成立是为了促进对6个遗传学的多中心合作研究 由数据协调中心(DCC)组织的研究中心(GRC)。我们约翰·霍普金斯大学的GRC (JHGRC)为IBDGC的所有研究做出了贡献，实现了招聘目标，并在IBDGC中发挥了作用 领导地位。我们特别关注非裔美国人(AA)IBD遗传学。我们表演了第一个 对AA群体中的欧洲基因座进行大规模评估，复制了几个基因，但也发现了独特的 这些基因座中的非洲-祖先变异，以及识别出多个混合显著基因座。我们也 发表了第一个AA IBD全基因组关联研究(GWAS)，这是一项合作努力，确定了两个 非洲特有的基因座，并复制了多个额外的欧洲基因座。我们还探讨了为什么有些人 在欧洲人和其他人群中具有已证实的风险变异的基因座只会在一个祖先中引起疾病 人口，而不是其他人。需要对再障IBD进行更多的研究，以了解该病的病因。 祖传不同的，主要的美国人口。在本申请中，我们将通过更好的方式重新评估AA GWAS 评估全基因组测序数据以测试低频率和稀有变异，并执行 X染色体变异的评估。我们将通过我们自己的和 多个卫星招聘中心，为第二个AA IBD GWA提供支持，包括UC和CD，并进行Meta-Analyst 首先识别更多新的基因座，识别更多非洲特有的风险变异，并复制已知的基因座用于 并复制我们的混合基因座。我们还将整合不同的数据源，以整合 包括目前在再生障碍性贫血淋巴母细胞系上产生的RNA-Seq CD病例和对照，以及我们将在UC病例和对照的结肠活检中产生的RNA-Seq。 我们将评估来自欧洲的IBD相关细胞类型的染色质差异和基因表达。 AA和东亚祖先，以更好地了解祖先的座位异质性。我们会 继续参与IBDGC的所有活动，以最大限度地发挥IBD遗传学研究的影响 合作筹资机制。

PROJECT SUMMARY Inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are complex genetic disorders of the gastrointestinal tract, and a major health burden to patients and society. Tremendous progress has been made in dissecting IBD genetic etiology with identification of over 200 IBD loci by genome wide association studies (GWAS) but mainly limited to persons of European ancestry. The IBD Genetics Consortium (IBDGC) was established to facilitate multicenter collaborative studies of 6 Genetics Research Centers (GRCs) organized with a Data Coordinating Center (DCC). Our GRC at Johns Hopkins (JHGRC) has contributed to all IBDGC studies, meeting recruitment objectives and taking roles in IBDGC leadership positions. Our particular focus is on African American (AA) IBD genetics. We performed the first large-scale evaluation of European loci in the AA population, replicating several genes, but also finding unique African-ancestral variants within these loci, as well as identified multiple admixture significant loci. We also published the first AA IBD genome-wide association study (GWAS), a collaborative effort that identified two African-specific gene loci, and replicated multiple additional European loci. We have also explored why some loci with proven risk variants in Europeans and other populations only cause disease in one ancestral population but not others. More research in AA IBD is needed to understand the etiology of IBD in this ancestrally distinct, major American population. In this application we will re-evaluate the AA GWAS by better imputation, evaluate whole genome sequencing data to test low frequency and rare variants, and perform an evaluation for chromosome X variants. We will recruit a large number of AA IBD patients through our own and multiple Satellite Recruitment Centers to power a second AA IBD GWAS, both UC and CD, and meta-analyze with the first to identify more novel loci, identify more African specific risk variants, and replicate known loci for this population and replicate our admixture loci. We will also incorporate diverse data sources to incorporate into our GWAS analyses including RNA-Seq currently being generated on lymophoblastoid cell lines from AA CD cases and controls, and RNA-Seq that we will generate in colonic biopsies from UC cases and controls. We will evaluate chromatin differences and expression of genes in cell types relevant to IBD from European, AA and East Asian ancestries in an effort to better understand locus heterogeneity by ancestry. We will continue to participate in all IBDGC activities to maximize the Impact of IBD genetics research by this cooperative funding mechanism.