Using polygenic scores to enhance both variant discovery, and understanding of functional consequences of genetic variation in IBD.

项目1： 炎症性肠病(IBD)、克罗恩病和溃疡性结肠炎在基因上是复杂的 在这些疾病中，环境也是一个重要因素。已经有200多种基因变异被发现 与IBD的发展有关，也有相当多的关于微生物组的见解 与IBD的关系。到目前为止，大多数基因研究都使用了旨在捕获 常见的遗传信号。我们已经证明，整个外显子组测序(WES)可以识别罕见的变异， 进一步加深了对IBD遗传结构的理解。我们的初步数据还表明， 创建多基因基因风险分数(GRS)可以为发现额外的基因增加一个强大的维度 这不仅有助于研究微生物信号，也有助于阐明与微生物组之间的复杂关系。在这项提案中，我们将 利用下一代测序方法，单细胞技术与新的基因和 系统生物学方法，以进一步了解IBD的根本原因。我们将产生额外的 IBD受试者的WES数据因其极端表型或GRS而被选择并丰富 无论是遗传群体还是极端表型群体，都可能进一步促进变异的发现。我们会 在健康对照和UC受试者中识别保护性变异体，这些受试者在遗传上已准备好发展为CD 遗传性的易患严重疾病的NFkB途径基因的遗传变异在 严重UC，我们将从具有高和低NFkB GRS的UC受试者中提取单核细胞，并进行 对这些受试者进行RNAseq和单细胞测序以更好地了解 这些基因变异。我们将扩展我们的显著观察结果，即GRS对 在对照和IBD病例中的粘膜代谢组，我们将扩大这些研究，以尝试和更好地 了解血清代谢组反映粘膜特征的能力。我们的初步数据显示 支持疾病和途径特异性GRS将识别IBD的分子极端/聚集性的假设 主题：促进新的变异发现；阐明IBD相关的功能影响 以及描述对宿主-微生物关系的遗传效应。

PROJECT 1: The Inflammatory Bowel Diseases (IBD), Crohn's disease and ulcerative colitis are genetically complex diseases in which the environment is also a significant contributor. More than 200 genetic variants have been associated with the development of IBD and there have also been considerable insights of microbiome associations with IBD. To date, most genetic studies have used platforms that are designed to capture common genetic signals. We have shown that whole exome sequencing (WES) can identify rare variants that add further to the understanding of the genetic structure of IBD. Our preliminary data also suggests that the creation of polygenic gene risk scores (GRS) can add a powerful dimension to discovering additional genetic signals and also to elucidating the complex relationship with the microbiome. In this proposal we will be utilizing next generation sequencing approaches, single cell technology, together with novel genetic and systems biology approaches to further understand the underlying causes of IBD. We will generate additional WES data in IBD subjects selected as a consequence of their extreme phenotypes or GRS and enriching populations either genetically or by extreme phenotype will likely enhance variant discovery further. We will identify protective variants in healthy controls genetically `primed' to develop CD and also in UC subjects genetically predisposed to severe disease. Genetic variation in genes of the NFkB pathway are enriched in severe UC and we will extract monocytes from UC subjects with high and low NFkB GRSs and perform RNAseq and single cell sequencing on these subjects to better understand the functional consequences of these genetic variants. We will expand upon our striking observation that GRS has a profound effect on the mucosal metabolome in both controls and IBD cases and we will extend these investigations to try and better understand the ability of the serum metabolome to reflect the mucosal signature. Our preliminary data strongly support the hypothesis that disease and pathway specific GRS will identify molecular extremes/clusters of IBD subjects: facilitating novel variant discovery; elucidating functional effects consequent of IBD-associated variants; and delineating genetic effects on host-microbiomal relationships.