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

Abstract

BackgroundVesicoureteral 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.MethodsA 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.ResultsAltogether, 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=6.35×10−8) 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 (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). 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=1.86×10–9). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis.ConclusionsThese 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.

Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT

“…37 In addition, copy number variants have been shown to cause CAKUT in up to 16.6% of cases. [38][39][40] In conclusion, we showed that a likely monogenic cause of CAKUT can be detected using ES and reverse phenotyping in 11.4% of families. We suggest that reverse phenotyping be systematically applied to families with CAKUT to increase the diagnostic yield of molecular genetic diagnostics.…”

Fully exploiting SNP arrays: a systematic review on the tools to extract underlying genomic structure

“…In particular, CNV genotyping was crucial in studies involving diseases such as schizophrenia [ 216 , 217 ], bipolar disorder [ 216 ], Parkinson’s disease [ 218 ], Autism Spectrum Disorder [ 219 ] and attention deficit hyperactivity disorder [ 220 ]. Other CNVs studies included different outcomes such as HBV [ 221 , 222 ], autophagy [ 223 ], gallstones disease [ 224 ], vesicoureteral reflux [ 225 ], esotropia [ 226 ], cheap screenings for primary immunodeficiency [ 227 ] and COVID-19 potential targets [ 228 ]. For these studies, PennCNV was the most popular, followed by Nexus Copy Number, Birdsuite and QuantiSNP.…”

Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

“…38 Many common variants associated with specific kidney function measures or complex kidney diseases have been identified through genome-wide association studies (GWAS) and exome-or genome-sequencing studies of large population samplesusually of European or East Asian ancestry (Figure 2). 13,14,17,19,31,[39][40][41] The largest number of locigenomic regions containing associated SNPs-were discovered for the continuous kidney function measure eGFR, with studies based on data from >1 million individuals reporting more than 250 such loci. [12][13][14]17,19,22,23,31,40, Although the distinction of monogenic versus polygenic diseases provides a useful practical framework, genetic risk variants for kidney diseases occur on a spectrum from rare variants with large effects to common variants with small effects, and many diseases do not fit neatly into either category.…”

“…13,14,17,19,31,[39][40][41] The largest number of locigenomic regions containing associated SNPs-were discovered for the continuous kidney function measure eGFR, with studies based on data from >1 million individuals reporting more than 250 such loci. [12][13][14]17,19,22,23,31,40, Although the distinction of monogenic versus polygenic diseases provides a useful practical framework, genetic risk variants for kidney diseases occur on a spectrum from rare variants with large effects to common variants with small effects, and many diseases do not fit neatly into either category. For example, apolipoprotein L1 (APOL1)associated kidney risk variants are common among some populations of African ancestry and impart a relatively high risk under a recessive mode of inheritance, but these variants are not considered monogenic.…”