Human genetic approaches to lower urinary tract phenotypes

项目1：项目总结/摘要 基因组技术，如外显子组测序和GWAS尚未系统地应用于大多数 良性泌尿表型之前，我们的工作在哥伦比亚奥布莱恩泌尿研究中心。我们有 已成功应用全基因组关联研究（GWAS）和罕见拷贝数变异分析， 鉴定与膀胱输尿管反流（VUR）相关的新基因和位点。 在这里，我们建议对VUR患者进行外显子组测序，以识别诊断性罕见单核苷酸 变异，并进行探索性VUR全外显子组关联研究。与微生物合作 基因组学生物医学核心，我们将对这些患者的尿液样本进行16 S rRNA测序， 与VUR和尿路感染（UTI）两者一起，以生成尿微生物群谱。我们将分析 微生物群特征与表型变异和结果以及与罕见遗传变异的关联，以及 进行微生物群落常见变异全基因组关联研究（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GWAS， 常见下尿路症状（LUTS）表型，随后进行表型全关联研究， 发现常见遗传病因的风险因素和合并症。 我们提出的研究将利用来自四个NIDDK资助的国家队列的现有数据和生物标本， RIVUR（UTI伴VUR）、CUTIE（UTI不伴VUR）、CKiD（儿科慢性肾脏疾病，包括返流 VUR）和LURN（LUTS）研究队列;以及两个大人群队列，其结合了联合收割机电子医疗 记录和基因组学，来自英国生物银行和NHGRI资助的eMERGE网络。拟议的研究 将为良性泌尿系统高度相关疾病的发病机制提供新的见解， 将基因检测引入泌尿科实践。

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.