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

Area of Science:

• Genetics
• Pediatric Nephrology
• Urology

Background:

• Vesicoureteral reflux (VUR) is a prevalent genetic disorder affecting the genitourinary system.
• It is a significant contributor to pediatric urinary tract infections (UTIs) and subsequent kidney failure.
• The underlying genetic basis of VUR remains incompletely understood.

Purpose of the Study:

• To investigate the genetic underpinnings of VUR by analyzing rare copy number variants (CNVs) and common genetic variants.
• To identify specific genetic risk factors associated with VUR in a large patient cohort.
• To explore the role of identified genes in urinary tract development.

Main Methods:

• Diagnostic analysis of rare pathogenic CNV disorders in 1737 VUR patients.
• Genome-wide association study (GWAS) in 1395 VUR patients and 5366 controls of European ancestry.
• Analysis of gene variants in developmental genes and validation in mouse models.

Main Results:

• Approximately 3% of VUR patients had undiagnosed rare CNV disorders (e.g., 1q21.1, 16p11.2, 22q11.21, Triple X syndromes).
• GWAS identified significant loci with large effect sizes, including variants in developmental genes like WDPCP, OTX1, BMP5, VANGL1, and WNT5A.
• A specific intronic variant in WDPCP (rs13013890) was strongly associated with VUR (OR=3.65), and Wnt5a signaling was confirmed in mouse models for its role in urinary tract development.

Conclusions:

• VUR exhibits significant genetic heterogeneity, with rare CNVs and common variants contributing to risk.
• A combined 6% of VUR patients carried a rare CNV or common variant genotype with an odds ratio greater than 3.
• These genetic findings have important implications for clinical management and understanding VUR outcomes.