Genetics and gene regulation in the inflammatory bowel diseases

!摘要 全基因组关联研究发现了200个与炎症性肠病相关的基因位点 疾病（IBD）。与其他同事一起，Hailiang Huang博士领导了最近的精细绘图工作， 国际IBD遗传学联盟，令人信服地将许多这些疾病关联映射到一个小的 一组具有高因果概率的变体。尽管如此，许多这些精细映射的因果变异都很接近 基因，其中很少有明确的功能。这个四年研究计划的提出，就是为了填补这一 通过开发和采用新的统计遗传学方法和分析， 了解组织特异性基因调控和IBD遗传学之间的联系。 通过计划中的培训和指导，黄博士将开发新的方法来识别顺式调节基因， 使用RNA的表达数量性状基因座和剪接数量性状基因座等元件 测序这些方法利用了等位基因特异性信息，但与现有方法不同， 不需要阶段知识。因此，本研究将确定以前遗漏的顺式调节变体 对于定相而言，其与具有有限连锁不平衡的基因是罕见的或遥远的。将使用表观基因组图谱 以凭经验鉴定疾病相关顺式调节元件可能在其中起作用的组织。损失- 也将整合破坏疾病相关组织特异性转录物同种型的无功能变体 在分析中。 此外，黄博士将使用一种新的方法对IBD关联进行精细映射， 个体基因分型和测序在各种平台上，并利用不同的联系不平衡 全世界人口的模式。将设计贝叶斯统计方法来理解 这些精细定位的IBD关联与组织特异性顺式调节元件之间的联系 在这个提议中。从这些分析中获得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，并生成一个最佳候选人的短列表， 可能性，以进行进一步的功能研究。本研究中设计的新方法也将在 软件包，并广泛提供给社区。 这项工作的成功完成将为黄博士提供深入的IBD生物学培训， 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的技能和专业知识，并从事专业和职业 发展活动，包括演讲，手稿准备和赠款写作。拟议 研究计划将导致未来的非编码基因组和IBD遗传学项目，黄博士将 做首席调查员

! 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.