Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux

Background Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and amajor cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood.Methods A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry.Results Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35x10(-8)) TheGWAS identified three studywide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, andWNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86x10(-9)). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis ofWnt5amutant mice confirmedthe roleofWnt5a signaling inbladder and uretericmorphogenesis.Conclusions These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.