Identification and characterization of inflammatory bowel disease causal variants

炎症性肠病致病变异的鉴定和表征

• 批准号: 10679091
• 负责人: Hailiang Huang
• 金额: $ 69.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679091
• 关键词: Address; Adolescence; Affect; African; Algorithms; American; Autoimmune Diseases; Binding Sites; Biological; Biology; CRISPR interference; CRISPR-mediated transcriptional activation; Cells; Chromosome Mapping; Chronic; Chronic Disease; Code; Data; Data Set; Digestive System Disorders; East Asian; Ensure; European; European ancestry; Gene Expression Regulation; Gene Frequency; Gene Targeting; Genetic; Genetic Diseases; Genetic study; Genome; Genomic Segment; Genomics; Genotype; Goals; Health Care Costs; Heritability; Heterogeneity; Histones; Human; Human Genetics; Individual; Inflammatory Bowel Diseases; International; Knock-in; Knowledge; Link; Linkage Disequilibrium; Maps; Meta-Analysis; Methodology; Methods; Molecular; Nature; Outcome; Pathogenesis; Pathway interactions; Persons; Population; Printing; Probability; Process; Quality Control; Resolution; Resources; Rest; Sample Size; Sampling; Series; Site; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Uncertainty; United States National Institutes of Health; Untranslated RNA; Variant; causal variant; cohort; data harmonization; design; disorder risk; emerging adult; exome sequencing; experimental study; genetic association; genetic technology; genetic variant; genome resource; genome wide association study; genomic data; genomic locus; genotyping technology; health disparity; improved; in silico; insight; novel; pleiotropism; protein function; success; transcription factor; web portal

PROJECT SUMMARY/ABSTRACT Inflammatory bowel diseases (IBD) are a group of chronic, debilitating disorders of the gastrointestinal tract with peak onset in adolescence and early adulthood. More than 3 million people are affected in U.S., with an estimated direct healthcare cost of $6.3 billion per year. IBD are highly heritable, thus, studying the genetic basis of IBD is a natural path towards elucidating the IBD pathogenesis, which is poorly understood at present. Genome-wide association studies have identified over 240 loci associated with IBD. These associations typically implicate large genomic regions with hundreds of variants due to the linkage disequilibrium (LD). The latest IBD fine-mapping study resolved the LD and mapped 45 IBD associations to single-variant resolution, providing insights into how genetic variants contribute to IBD pathogenesis in a tissue specific manner. Despite of this initial success, most IBD associations and putative causal variants to date were derived from European ancestries with uncertainty in their transferability to non-European ancestries; and the functional impact for most IBD causal variants, especially the noncoding variants, is unclear. This proposed study bridges these gaps through an integrative strategy combining fine-mapping on a large-scale multi-ancestry IBD cohort and well-designed functional experiments to investigate the genetic basis of IBD. This cohort includes subjects of four ancestral populations including African, admixed American, East Asian and European, with an unprecedented sample size of over 192,600 IBD cases, 3x, 12x, 5x and 3x of the current IBD sample size for each ancestry respectively. A large amount of exome sequencing (WES) data will be included, allowing us to investigate the contribution from rare coding variants which have been shown to be important to IBD and help to link noncoding variants to their gene targets. Extensive quality control and harmonization will be performed to generate a high quality, high coverage individual-level dataset with minimal heterogeneity across ancestries, technologies, and batches. A novel fine-mapping method will be developed to leverage the genomic diversity across ancestries and the WES data with the goal to enhance the fine-mapping resolution especially in the coding genome. Over 200 new IBD causal variants are expected from this study, including many that have large effects and directly disrupt protein functions. These variants will be characterized for their molecular and cellular mechanism in IBD in human T cells using pooled CRISPR activation and CRISPR interference experiments, and knockins of coding variants for their effects on gene regulation in resting and stimulated cells. The new IBD causal variants and biology from this study will provide new insights into IBD pathogenesis, make important positive impact and serve as the fundamental resource and basis toward novel IBD therapeutics.

项目摘要/摘要 炎症性肠病（IBD）是一群胃肠道的慢性，使人衰弱的疾病 青春期和成年初期的峰值发作。在美国有超过300万人受到影响， 估计直接医疗保健费用为每年63亿美元。 IBD是高度遗传的，因此研究遗传基础 IBD的自然途径是阐明IBD发病机理，目前尚未理解。 全基因组关联研究已经确定了与IBD相关的240个基因座。这些关联 通常，由于连锁不平衡（LD），大型基因组区域具有数百种变体。这 最新的IBD精细映射研究解决了LD，并将45个IBD关联映射到单变量分辨率， 提供有关遗传变异如何在组织特异性方式中促进IBD发病机理的见解。尽管 在这一最初的成功中，迄今为止，大多数IBD协会和推定的因果变体均来自欧洲 其转移到非欧洲祖先的不确定性的祖先；以及大多数的功能影响 IBD因果变体，尤其是非编码变体，尚不清楚。 这项拟议的研究通过结合精细映射的综合策略来弥合这些差距 大规模多功能IBD队列和精心设计的功能实验，以研究遗传基础 IBD。该队列包括四个祖先人口的主题 亚洲和欧洲，前所未有的样本量超过192,600个IBD案例，3倍，12倍，5倍和3倍 每个祖先的当前IBD样本大小。大量外显子组测序（WES）数据将 包括在内，允许我们调查稀有编码变体的贡献 对IBD很重要，并有助于将非编码变体与其基因靶标联系起来。广泛的质量控制和 将进行协调以生成高质量的高覆盖范围的个人级数据集，而最少 祖先，技术和批次之间的异质性。将开发出一种新颖的精细映射方法 利用祖先的基因组多样性和WES数据的目标，以增强细映射 解决方案，尤其是在编码基因组中。从这项研究中，预计有200多个新的IBD因果变体， 包括许多具有较大作用并直接破坏蛋白质功能的人。这些变体将被描述 使用合并的CRISPR激活和CRISPR，用于IBD中IBD中的分子和细胞机制 干涉实验和编码变体的敲门蛋白，以对静止和静止和 刺激的细胞。 这项研究的新的IBD因果变异和生物学将为IBD发病机理提供新的见解， 产生重要的积极影响，并作为新型IBD治疗剂的基本资源和基础。