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：
10700954
负责人：
ALI G GHARAVI
金额：
$ 24.21万
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/10700954
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 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 Reflux Research Risk Risk Factors Role Sampling Shapes Signal Transduction Single Nucleotide Polymorphism Symptoms Technology Urinary Incontinence Urinary Microbiome Urinary tract infection Urine Urology Urothelium Variant Vesico-Ureteral Reflux Visit WNT5A gene Work biobank clinical care clinical diagnosis clinical phenotype cohort comorbidity cost diagnostic value empowerment exome exome sequencing experience follow-up genetic approach genetic testing genetic variant genome sequencing genome wide association study genomic data 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/摘要大多数基因组技术（例如外显子组测序和GWAS）尚未系统地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的良性泌尿外科表型。我们有已经成功应用全基因组关联研究（GWAS）和罕见的拷贝数变体分析识别与囊层反射X（VUR）相关的新型基因和位置。在这里，我们建议执行VUR患者的外显子体序列以鉴定诊断稀有的单核苷酸变体并进行探索性vur整个外显着联想研究。与微生物合作基因组生物医学核心我们将从这些患者的尿液样本中进行16S rRNA测序，与VUR和尿路感染（UTI）一起产生尿菌群谱。然后我们将分析与表型变异和结果以及稀有遗传变异的微生物群谱相关，以及执行微生物群变体基因组结合研究（MGWAS）。为了将这些基因组研究扩展到其他重要的泌尿科表型，我们将执行常见的较低尿路症状（LUTS）表型，然后进行全球范围的关联研究发现具有常见遗传病因的危险因素和合并症。我们拟议的研究将利用来自四个NIDDK资助的国家人群的现有数据和生物测量， Rivur（带有VUR的UTI），可爱（无VUR的UTI），CKID（小儿慢性肾脏疾病，包括反流 VUR）和Lurn（LUTS）研究队列；以及两个结合电子医疗的大量人群来自英国生物银行和NHGRI资助的Emerge Network的记录和基因组学。提出的研究将提供有关与良性泌尿科高相关性疾病的发病机理的新见解，并促进将基因检测引入泌尿外科实践。