Human genetic approaches to lower urinary tract phenotypes

降低尿路表型的人类遗传学方法

基本信息

批准号：
10297545
负责人：
ALI G GHARAVI
金额：
$ 22.85万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-24 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297545
关键词：
16S ribosomal RNA sequencing 16p11.2 Address Animal Model BMP5 gene Benign Biological Assay Childhood Chronic Kidney Failure Cohort Studies Collaborations Complex Computerized Medical Record Copy Number Polymorphism Data Diagnostic Disease Dysuria Effectiveness Electronic Health Record Electronic Medical Records and Genomics Network Ensure Event Functional disorder Funding Genes Genetic Genetic Diseases Genetic Predisposition to Disease Genomics Homeostasis Human Genetics Investigation Literature Longterm Follow-up Lower urinary tract Measurement Metabolic Morbidity - disease rate National Human Genome Research Institute National Institute of Diabetes and Digestive and Kidney Diseases Obstruction Outcome Pathogenesis Pathway interactions Patients Pelvic floor structure Phenotype Population Ptosis Questionnaires Research Risk Risk Factors Role Sampling Shapes Signal Transduction Single Nucleotide Polymorphism Symptoms Technology Urinary Incontinence Urinary Microbiome Urinary tract Urinary tract infection Urine Urology Urothelium Variant Vesico-Ureteral Reflux Visit WNT5A gene Work biobank clinical Diagnosis clinical care clinical phenotype cohort comorbidity cost exome exome sequencing experience follow-up genetic approach genetic testing genetic variant genome sequencing genome wide association study genomic data genomic locus improved insight lower urinary tract symptoms malformation microbial community microbial genomics microbiome microbiota microbiota profiles novel patient subsets phenome proband rare variant response to injury sex trait urinary urologic

项目摘要

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.

项目 1：项目摘要/摘要外显子组测序和 GWAS 等基因组技术尚未在大多数国家得到系统应用。在我们在哥伦比亚奥布莱恩泌尿学研究中心工作之前，我们已经了解了良性泌尿表型。已经成功地将全基因组关联研究（GWAS）和罕见拷贝数变异分析应用于识别与膀胱输尿管反流（VUR）相关的新基因和基因座。在这里，我们建议对 VUR 患者进行外显子组测序，以鉴定诊断性稀有单核苷酸变体并与 Microbial 合作进行探索性 VUR 全外显子组关联研究。 Genomics Biomedical Core 我们将从一组患者的尿液样本中进行 16S rRNA 测序，然后我们将结合 VUR 和尿路感染 (UTI) 来生成尿液微生物群谱并进行分析。微生物群概况与表型变异和结果以及罕见遗传变异的关联，以及进行微生物群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表型，我们将进行 GWAS 常见的下尿路症状（LUTS）表型，然后进行全表组关联研究发现具有常见遗传病因的危险因素和合并症。我们提出的研究将利用来自 NIDDK 资助的四个国家队列的现有数据和生物样本， RIVUR（伴有 VUR 的 UTI）、CUTIE（不伴有 VUR 的 UTI）、CKiD（儿童慢性肾病，包括反流） VUR）和 LURN (LUTS) 研究队列；以及两个结合电子医学的大型人群队列；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，并促进将基因检测引入泌尿外科实践。