IBD Gene Mapping by Clinical and Population Subset

按临床和人群亚群划分的 IBD 基因图谱

• 批准号: 9402477
• 负责人: Steven R Brant
• 金额: $ 50.56万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402477
• 关键词: ATAC-seq; Admixture; African; African American; Algorithms; American; Asians; Biopsy; Caring; Cell Line; Centers for Disease Control and Prevention (U.S.); Charge; Chromatin; Chromosome Mapping; Chronic; Clinical; Coculture Techniques; Cohort Studies; Collaborations; Complex; Crohn' s disease; DNA; Data; Data Coordinating Center; Data Sources; Databases; Disease; Effectiveness; Enhancers; Epithelium; Ethnic Origin; Etiology; European; Evaluation; Fostering; Frequencies; Funding; Funding Mechanisms; Future; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Research; Genetic Variation; Genotype; Goals; Health; Hereditary Disease; Heterogeneity; Hispanics; Human Characteristics; Individual; Inflammatory Bowel Diseases; Investigation; Lead; Leadership; Linkage Disequilibrium; Machine Learning; Medical; Modeling; Nature; Other Genetics; Pathway Analysis; Patients; Pattern; Persons; Phase; Phenotype; Point Mutation; Population; Population Genetics; Positioning Attribute; Prevalence; Preventive measure; Publications; Publishing; Quality of Care; Recruitment Activity; Research; Resources; Role; Sampling; Societies; Source; Testing; Ulcerative Colitis; Universities; Update; Variant; Work; X Chromosome; base; case control; cell type; differential expression; disorder prevention; experience; genetic association; genome sequencing; genome wide association study; improved; insight; interest; macrophage; meetings; novel; novel strategies; racial disparity; rare variant; risk variant; sex; study population; transcriptome sequencing; two-dimensional; whole genome

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.

项目摘要 炎症性肠病 (IBD)、克罗恩病 (CD) 和溃疡性结肠炎 (UC) 胃肠道的复杂遗传性疾病，给患者和社会带来重大健康负担。 通过鉴定 200 多个 IBD 位点，剖析 IBD 遗传病因学取得了巨大进展 通过全基因组关联研究（GWAS），但主要限于欧洲血统的人。炎症性肠病 遗传学联盟（IBDGC）的成立是为了促进 6 种遗传学的多中心合作研究 研究中心 (GRC) 与数据协调中心 (DCC) 共同组织。我们在约翰·霍普金斯大学的 GRC (JHGRC) 为所有 IBDGC 研究做出了贡献，实现了招聘目标并在 IBDGC 中发挥了作用 领导职位。我们特别关注非裔美国人 (AA) IBD 遗传学。我们表演了第一场 对 AA 群体中的欧洲基因座进行大规模评估，复制了多个基因，但也发现了独特的 这些基因座内的非洲祖先变异，以及确定的多个混合显着基因座。我们也 发表了第一个 AA IBD 全基因组关联研究 (GWAS)，这是一项合作成果，确定了两个 非洲特有的基因位点，并复制了多个额外的欧洲基因位点。我们还探讨了为什么有些 在欧洲人和其他人群中已证实具有风险变异的基因座仅在一个祖先中引起疾病 人口，但不是其他人。需要对 AA IBD 进行更多研究以了解 IBD 的病因学 祖先独特的美国主要人口。在此应用中，我们将通过更好的方法重新评估 AA GWAS 插补，评估全基因组测序数据以测试低频和罕见变异，并执行 X 染色体变异的评估。我们将通过我们自己和招募大量的AA IBD患者 多个卫星招募中心为第二个 AA IBD GWAS（UC 和 CD）以及荟萃分析提供支持 第一个识别更多新基因座，识别更多非洲特定风险变异，并复制已知基因座 这个群体并复制我们的混合基因座。我们还将整合不同的数据源来整合 进入我们的 GWAS 分析，包括目前在 AA 类淋巴母细胞系上生成的 RNA 测序 CD 病例和对照，以及我们将从 UC 病例和对照的结肠活检中生成的 RNA-Seq。 我们将评估来自欧洲、欧洲和欧洲的与 IBD 相关的细胞类型的染色质差异和基因表达。 AA 和东亚血统，以更好地了解血统的基因座异质性。我们将 继续参与所有 IBDGC 活动，以最大限度地发挥 IBD 遗传学研究的影响 合作资助机制。