| Abstract: | Primary vesicoureteral reflux (pVUR) is one of the most common causes of pediatric kidney failure. Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance. Absence of pVUR in parents of affected individuals raises the possibility of a recessive contribution to pVUR. We performed a genome-wide linkage scan in 12 large families segregating pVUR, comprising 72 affected individuals. To avoid potential misspecification of the trait locus, we performed a parametric linkage analysis using both dominant and recessive models. Analysis under the dominant model yielded no signals across the entire genome. In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping. This interval achieved a peak heterogeneity LOD score of 3.6 with 60% of families linked. This heterogeneity LOD score improved to 4.5 with exclusion of two high-density pedigrees that failed to link across the entire genome. The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations. In conclusion, this study identifies a major new locus for pVUR and suggests that in addition to genetic heterogeneity, recessive contributions should be considered in all pVUR genome scans.Vesicoureteral reflux (VUR; OMIM no. 193000) is the retrograde flow of urine from the bladder to the ureters and the kidneys during micturation. Uncorrected, VUR can lead to repeated urinary tract infections, renal scarring and reflux nephropathy, accounting for up to 25% of pediatric end stage renal disease.1,2 VUR is commonly seen as an isolated disorder (primary VUR; pVUR), but it can also present in association with complex congenital abnormalities of the kidney and urinary tract or with specific syndromic disorders, such as renal-coloboma and branchio-oto-renal syndromes.3–8pVUR has a strong hereditary component, with monozygotic twin concordance rates of 80%.9–12 Sibling recurrence rates of 30% to 65% have suggested segregation of a single gene or oligogenes with large effects.9,12–14 Interestingly however, the three published genome-wide linkage scans of pVUR have strongly suggested multifactorial determination.15–17 Two pVUR loci have been identified with genome-wide significance on chromosomes 1p13 and 2q37 under an autosomal dominant transmission with locus heterogeneity.15,16 Multiple suggestive signals have also been reported, but remarkably, these studies show little overlap.15–17 These data suggest that pVUR may be extremely heterogeneous, with mutations in different genes each accounting for a fraction of cases. The genes underlying pVUR loci have not yet been identified, but two recent studies have reported segregating mutations in the ROBO2 gene in up to 5% of pVUR families.18,19Despite evidence for genetic heterogeneity and different subtypes of disease, genetic studies have all modeled pVUR as an autosomal dominant trait.15–17,20 Recessive inheritance has generally not been considered because the absence of affected parents can be explained by spontaneous resolution of pVUR with older age. However, many pVUR cohorts are composed of affected sibships or pedigrees compatible with autosomal recessive transmission, suggesting the potential for alternative modes of inheritance.9–12,16,17,20–22 Systematic family screening to clarify the mode of inheritance is not feasible for pVUR because the standard diagnostic tool, the voiding cystourethrogram (VCUG), is invasive and would expose participants to radiation. Formal assessment of a recessive contribution in sporadic pVUR has also been difficult because studies have been conducted in populations with low consanguinity rates.9–12,16,17,20–22 However, recent studies have identified an unexpected recessive contribution to several complex traits such as ductus arteriosus or autism.23,24 Thus, in addition to genetic heterogeneity, genes with alternative modes of transmission may segregate among pVUR families, and misspecification of the inheritance model may complicate mapping studies of this trait.Several approaches can be considered to address the difficulties imposed by complex inheritance, variable penetrance, and genetic heterogeneity. Studying large, well characterized cohorts with newer single-nucleotide polymorphism (SNP)-based technologies can maximize inheritance information across the genome and increase the power of linkage studies.25 In addition, in the setting of locus heterogeneity and uncertainty about the mode of transmission, analysis under a dominant and a recessive model has greater power compared with nonparametric methods and more often results in detection of the correct mode of transmission without incurring a significant penalty for multiple testing.26–29 We combined these approaches in this study and successfully localized a major gene for VUR, which unexpectedly demonstrates autosomal recessive transmission. |
