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

摘要: Background Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and major cause of pediatric urinary tract infection (UTI) kidney failure. The genetic basis VUR not well understood. Methods A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. GWAS was performed in 1395 5366 controls, European ancestry. Results Altogether, 3% harbored an undiagnosed rare CNV such as the 1q21.1, 16p11.2, 22q11.21, triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10-8) identified three study-wide significant five suggestive loci large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed developing (WDPCP, OTX1, BMP5, VANGL1, WNT5A). In particular, 3.3% were homozygous for intronic WDPCP (rs13013890; OR, 3.65; 2.39 5.56; P=1.86×10-9). This locus associated multiple phenotypes UK Biobank eMERGE studies. Analysis Wnt5a mutant mice confirmed role signaling bladder ureteric morphogenesis. Conclusions These data demonstrate heterogeneity 6% or common genotype conferring OR >3. Identification these risk factors has implications clinical care outcomes