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

使用多基因评分来增强 IBD 变异发现和对遗传变异功能后果的理解。

• 批准号: 9342775
• 负责人: Dermot Patrick McGovern
• 金额: $ 36.6万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9342775
• 关键词: Accounting; Address; Adopted; Autophagocytosis; Behavior; Cells; Collaborations; Complex; Crohn' s disease; Data; Development; Dimensions; Disease; Disease Pathway; Disease susceptibility; Employee Strikes; Environment; First Degree Relative; Genes; Genetic; Genetic Predisposition to Disease; Genetic Structures; Genetic Variation; Genetic study; Genotype; Individual; Inflammatory Bowel Diseases; Investigation; Kinetics; Ligands; Medical; Modeling; Molecular; Natural History; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Predisposition; Refractory; Resolution; Risk; Role; Serologic tests; Serum; Severities; Signal Transduction; Systems Biology; Technology; Testing; Ulcerative Colitis; Variant; base; clinical phenotype; cohort; design; exome sequencing; experimental study; falls; follow-up; genetic association; genetic variant; innovation; insight; interest; metabolome; microbiome; monocyte; network models; next generation sequencing; novel; rare variant; response; risk variant; single cell sequencing; single cell technology; transcriptome; transcriptome sequencing

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.

项目1： 炎症性肠病 (IBD)、克罗恩病和溃疡性结肠炎的基因非常复杂 环境也是造成疾病的一个重要因素。已发现超过200个基因变异 与 IBD 的发展相关，并且对微生物组也有相当多的见解 与 IBD 的关联。迄今为止，大多数遗传学研究都使用旨在捕获 常见的遗传信号。我们已经证明，全外显子组测序 (WES) 可以识别罕见的变异， 进一步加深对 IBD 遗传结构的了解。我们的初步数据还表明 多基因基因风险评分（GRS）的创建可以为发现额外的遗传因素增加一个强大的维度 信号并阐明与微生物组的复杂关系。在本提案中，我们将 利用下一代测序方法、单细胞技术以及新颖的遗传和 系统生物学方法进一步了解 IBD 的根本原因。我们将生成额外的 IBD 受试者的 WES 数据因其极端表型或 GRS 而被选择，并丰富 遗传或极端表型的群体可能会进一步增强变异的发现。我们将 识别健康对照中基因“引发”发展 CD 的保护性变异以及 UC 受试者的保护性变异 具有罹患严重疾病的遗传倾向。 NFkB 通路基因的遗传变异丰富于 严重的 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 对这些主题进行 RNAseq 和单细胞测序，以更好地了解这些主题的功能后果 这些基因变异。我们将进一步阐述我们的惊人观察，即 GRS 对 对照和 IBD 病例中的粘膜代谢组，我们将扩展这些研究以尝试更好 了解血清代谢组反映粘膜特征的能力。我们的初步数据强烈 支持疾病和途径特异性 GRS 将识别 IBD 分子极端/簇的假设 主题：促进新变体的发现；阐明 IBD 相关的功能效应 变体；并描述遗传对宿主-微生物关系的影响。