Project One
A genomics approach to vesicoureteric reflux and other benign urological conditions such as Lower Urinary Tract symptoms (LUTS)
PI: Ali Gharavi, M.D.
In our O’Brien Center project, we are undertaking a genomics approach to study the genetic basis of vesicoureteral reflux (VUR) and other benign urological conditions such as Lower Urinary Tract symptoms (LUTS). To date we have applied GWAS methodology and copy number variant (CNV) analysis to identify genes for VUR. In an analysis of over 1700 VUR cases, we found that 3% of cases harbor an undiagnosed rare CNV disorder such as the 1q21.1, 16p11.2, 22q11.21 and Triple X syndromes (OR = 3.1; p = 6.5 x 10-8). The GWAS identified 3 study-wide significant and 5 suggestive loci with large effects (ORs = 1.41 to 6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1 and WNT5A). The WDPCP locus was associated with multiple genitourinary phenotypes in the UKBiobank and eMERGE studies. In collaboration with the Mendelsohn lab, we study of Wnt5a mutant mice, which confirmed the role Wnt5a signaling in bladder and ureteric morphogenesis.
Figure. Concentric Manhattan plot showing mapping of new risk loci for VUR via GWAS (L). Excess burden of large CNVs in VUR (R).
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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 a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood.Methods: We performed a diagnostic analysis for rare, pathogenic copy number variant (CNV) disorders in 1,737 cases. We also conducted a GWAS in 1,395 cases and 5,366 controls of European ancestry.
Results: Altogether, 3% of VUR cases harbored an undiagnosed rare CNV disorder such as the 1q21.1, 16p11.2, 22q11.21 and Triple X syndromes (OR = 3.1; p = 6.5 x 10-8). The GWAS identified 3 study-wide significant and 5 suggestive loci with large effects (ORs = 1.41 to 6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1 and WNT5A). In particular, 3.3% of VUR cases were homozygous for an intronic variant in WDPCP (rs13013890; OR = 3.7; 95% CI = 2.39 – 5.56; P = 1.86 x 10-9). This locus was associated with multiple genitourinary phenotypes in the UKBiobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role Wnt5a signaling in bladder and ureteric morphogenesis.
Conclusions: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of VUR patients 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.