Human genetic approaches to lower urinary tract phenotypes

项目1：项目摘要/摘要 基因组技术，如外显子组测序和遗传多样性分析，在大多数情况下还没有得到系统的应用 在我们在哥伦比亚奥布莱恩泌尿外科研究中心工作之前，良性的尿路表型。我们有 已经成功地将全基因组关联研究和稀有拷贝数变异分析应用于 发现与膀胱输尿管反流(VUR)相关的新基因和新基因。 在这里，我们建议对VUR患者进行外显子组测序，以识别诊断罕见的单核苷酸 并进行了一项探索性的VUR整个外显子组关联研究。与微生物公司合作 基因组学生物医学核心我们将从一组患者的尿样中进行16S rRNA测序， 使用VUR和尿路感染(UTI)来生成尿菌群图谱。然后我们将分析和分析 微生物区系图谱与表型变异和结果以及罕见的遗传变异相关 进行微生物区系-常见变异体全基因组关联研究(MGwas)。 为了将这些基因组研究扩展到其他重要的良性泌尿系统表型，我们将进行 常见下尿路症状(LUTS)表型，随后进行表型全组关联研究 发现常见遗传病因的危险因素和共病。 我们提议的研究将利用NIDDK资助的四个国家队列的现有数据和生物谱， RIVUR(有VUR的UTI)，CUTIE(无VUR的UTI)，CKiD(儿童慢性肾脏疾病，包括反流) VUR)和Lurn(LUTS)研究队列；以及两个结合了电子医疗的大型人群队列 记录和基因组学，来自英国生物库和NHGRI资助的Emerge网络。建议进行的研究 将为与良性泌尿外科高度相关的疾病的发病机制提供新的见解，并有助于 将基因检测引入泌尿外科实践。

PROJECT 1: PROJECT SUMMARY/ABSTRACT Genomic technologies such as exome sequencing and GWAS have not been systematically applied for most benign urological phenotypes prior to our work at the Columbia O’Brien Urology Research Center. We have already successfully applied genome-wide association study (GWAS) and rare copy-number variant analysis to identify novel genes and loci associated with vesicoureteral reflux (VUR). Here we propose to perform exome sequence of VUR patients to identify diagnostic rare single nucleotide variants and perform an exploratory VUR whole exome association study. In collaboration with the Microbial Genomics Biomedical Core we will conduct 16S rRNA sequencing from urine samples of a set of these patients, with both VUR and urinary tract infections (UTI) to generate urinary microbiota profiles. We will then and analyze microbiota profile associations with phenotypic variants and outcomes and with rare genetic variants, and perform a microbiota-common variant genome-wide association study (mGWAS). To extend these genomic studies to other important benign urology phenotypes we will perform a GWAS of common lower urinary tract symptoms (LUTS) phenotypes, followed by phenome-wide association study to uncover risk factors and comorbidities with common genetic etiology. Our proposed studies will leverage existing data and biospecimens from four NIDDK-funded national cohorts, the RIVUR (UTI with VUR), CUTIE (UTI without VUR), CKiD (pediatric chronic kidney disease, including reflux VUR) and LURN (LUTS) study cohorts; as well as two large population cohorts that combine electronic medical records and genomics, from the UK Biobank and the NHGRI-funded eMERGE network. The proposed studies will provide new insight into the pathogenesis of disorders of high relevance to benign urology and also facilitate introduction of genetic testing into the practice of Urology.