Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.
case_control · Level III
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- Also identified by DOI 10.1681/ASN.2020050681 and PMC identifier 8017540.
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Abstract
Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. 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. 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; <i>P</i>=6.35×10<sup>-8</sup>) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract (<i>WDPCP, OTX1, BMP5, VANGL1,</i> and <i>WNT5A</i>). In particular, 3.3% of VUR patients were homozygous for an intronic variant in <i>WDPCP</i> (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; <i>P</i>=1.86×10<sup>-9</sup>). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of <i>Wnt5a</i> mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. 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.