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.