Genetics and gene regulation in the inflammatory bowel diseases

炎症性肠病的遗传学和基因调控

• 批准号: 9751298
• 负责人: Hailiang Huang
• 金额: $ 14.45万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751298
• 关键词: Adolescence; Affect; Algorithms; Alleles; Alternative Splicing; Automobile Driving; Bayesian Method; Biology; Chronic; Chronic Disease; Code; Communities; Computational Biology; Computer software; Data; Data Set; Disease; Distant; Ethnic Origin; Etiology; Family; Future; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genome; Genotype; Genotype-Tissue Expression Project; Goals; Grant; Health Care Costs; Individual; Inflammatory Bowel Diseases; Inherited; International; Knowledge; Linkage Disequilibrium; Manuscripts; Maps; Mentors; Methods; Outcome; Outcome Study; Pattern; Performance; Phase; Population; Preparation; Principal Investigator; Probability; Protein Isoforms; Quantitative Trait Loci; RNA Splicing; Regulator Genes; Regulatory Element; Research; Research Design; Research Proposals; Techniques; Tissues; Training; Transcript; Untranslated RNA; Variant; Work; Writing; analytical method; base; career development; causal variant; cohort; design; differential expression; emerging adult; epigenomics; exome; experience; genome wide association study; improved; insight; loss of function; method development; novel; rare variant; skills; transcriptome; transcriptome sequencing

! ABSTRACT Genome-wide association studies have found 200 genetic loci associated with the inflammatory bowel diseases (IBD). With other colleagues, Dr. Hailiang Huang led the recent fine-mapping effort in the international IBD genetics consortium and convincingly mapped many of these disease associations to a small set of variants with high causal probabilities. Despite that a lot of these fine-mapped causal variants are near genes, few of them have well characterized functions. This four-year research plan is proposed to fill in this knowledge gap by developing and employing novel statistical genetics methods and analyses to systematically understand the connection between tissue-specific gene regulation and IBD genetics. With the planned training and mentoring, Dr. Huang will develop novel methods to identify cis-regulatory elements such as the expression quantitative trait loci and the splice quantitative trait loci using RNA sequencing. These methods take advantage of the allele specific information, but unlike existing methods, do not require the knowledge of phase. As a result, this study will identify previously missed cis-regulatory variants that are rare or distant to genes with limited linkage-disequilibrium for phasing. Epigenomic profiles will be used to empirically identify tissues that the disease associated cis-regulatory elements are likely to function in. Loss- of-function variants disrupting transcript isoforms specific to the disease relevant tissues will also be integrated in the analysis. Furthermore, Dr. Huang will perform fine-mapping for IBD associations using a novel method that combines individuals genotyped and sequenced on various platforms, and leverages the distinct linkage-disequilibrium patterns from worldwide populations. A Bayesian statistical method will be designed to understand the connection between these fine-mapped IBD associations and tissue specific cis-regulatory elements identified in this proposal. Knowledge from these analyses will greatly improve our understanding of the non-coding genome and their impact on IBD, and generate a short list of the best candidates, ranked with their causal probabilities, for further functional studies. Novel methods designed in this study will also be implemented in software packages and made widely available to the community. Successful completion of this work will provide Dr. Huang in-depth training in IBD biology, the biology of transcriptome and gene regulations. Dr. Huang will also gain practical experience with RNA sequencing, acquire skills and expertise in statistical genetics method development, and engage in professional and career development activities including presentation, manuscript preparation and grant writing. The proposed research plan will lead to future projects in the non-coding genome and IBD genetics in which Dr. Huang will be the principal investigator.

好了！摘要 全基因组关联研究发现了200个与炎症性肠炎相关的遗传基因 疾病(IBD)。与其他同事一起，黄海良博士领导了最近在 国际IBD遗传学联合会，并令人信服地将其中许多疾病关联映射到一个小的 一组具有很高因果概率的变种。尽管如此，许多这些精细绘制的因果变量已经接近 基因，它们中很少有具有良好特征的功能。这项为期四年的研究计划就是为了填补这一空白而提出的 通过开发和使用新的统计遗传学方法和分析来系统地 了解组织特异性基因调控和IBD遗传学之间的联系。 在计划的培训和指导下，黄博士将开发新的方法来识别顺式调控 利用RNA表达数量性状基因座和剪接数量性状基因座等元素 测序。这些方法利用了等位基因特有的信息，但与现有方法不同的是，它们确实 不需要相的知识。因此，这项研究将确定以前遗漏的顺式调控变体 这些基因是罕见的或远离有限连锁的基因--阶段不平衡。将使用表观基因组图谱 经验性地确定与疾病相关的顺式调控元件可能在其中发挥作用的组织。损失- 破坏疾病相关组织特异性转录异构体的功能变异也将被整合 在分析中。 此外，黄博士将使用一种新的方法对IBD关联进行精细绘制，该方法结合了 个体在不同的平台上进行基因分型和测序，并利用明显的连锁不平衡 来自世界各地人口的模式。将设计一种贝叶斯统计方法来理解 这些精细定位的IBD关联与已识别的组织特异性顺式调控元件之间的联系 在这份提案中。来自这些分析的知识将极大地提高我们对非编码的理解 基因组及其对IBD的影响，并生成最佳候选者的简短列表，根据它们的因果关系进行排名 概率，用于进一步的功能研究。这项研究中设计的新方法也将在 软件包，并向社区广泛提供。 这项工作的成功完成将为黄博士提供IBD生物学方面的深入培训， 转录组和基因调控。黄博士还将获得RNA测序的实践经验， 获得统计遗传学方法开发方面的技能和专业知识，并从事专业和职业 发展活动，包括演示、手稿准备和赠款撰写。建议数 研究计划将导致非编码基因组和IBD遗传学的未来项目，黄博士将在这些项目中 做首席调查员。