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.

呢抽象的 全基因组关联研究发现了200个与炎症性肠相关的遗传基因座 疾病（IBD）。 Hailiang Huang博士与其他同事一起领导了最近的精细映射工作 国际IBD遗传学财团，令人信服地将许多疾病关联映射到一个小的 具有高因果概率的一组变体。尽管有很多这些精细的因果变体已经接近 基因，其中很少有人具有良好的功能。提出了这项为期四年的研究计划来填补这一点 通过开发和采用新颖的统计遗传学方法并进行分析来系统地进行知识差距 了解组织特异性基因调节与IBD遗传学之间的联系。 通过计划的培训和指导，黄博士将开发新的方法来识别顺式调节 使用RNA等元素，例如表达定量性状基因座和剪接定量性状基因座 测序。这些方法利用了等位基因的特定信息，但是与现有方法不同， 不需要相位的知识。结果，这项研究将确定先前错过的顺式调节变体 罕见或距离具有有限的链接式排序的基因，用于相位。将使用表观基因组轮廓 从经验上确定与疾病相关的顺式调节元件可能起作用的组织。损失 - 功能变体破坏了特定疾病相关组织的转录本的同工型 在分析中。 此外，黄博士将使用一种结合的新方法对IBD关联进行精细映射 在各种平台上进行了基因分型和测序的个体，并利用了独特的链接折线 来自全球人口的模式。将设计一种贝叶斯统计方法来了解 这些精细映射的IBD关联与组织特定顺式调节元件之间的联系 在此提案中。这些分析中的知识将大大提高我们对非编码的理解 基因组及其对IBD的影响，并产生了最佳候选人的简短清单，并以其因果关系排名 概率，用于进一步的功能研究。本研究中设计的新方法也将在 软件包，并为社区广泛使用。 这项工作的成功完成将为Huang博士提供IBD生物学的深入培训，即 转录组和基因法规。黄博士还将获得RNA测序的实用经验， 获取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 开发活动，包括介绍，手稿准备和赠款写作。提议 研究计划将导致黄博士将在非编码基因组和IBD遗传学的未来项目中 成为主要研究员。