title: A recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13.
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.
authors.affiliation: Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Weng
authors.forename: Simone
authors.initials: S
authors.lastname: Sanna-Cherchi
authors.forename: Terry
authors.initials: T
authors.lastname: Hensle
authors.forename: Ellen
authors.initials: E
authors.lastname: Shapiro
authors.forename: Alan
authors.initials: A
authors.lastname: Werzberger
authors.forename: Gianluca
authors.initials: G
authors.lastname: Caridi
authors.forename: Claudia
authors.initials: C
authors.lastname: Izzi
authors.forename: Anita
authors.initials: A
authors.lastname: Konka
authors.forename: Adam C
authors.initials: AC
authors.lastname: Reese
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.forename: Samuel
authors.initials: S
authors.lastname: Werzberger
authors.forename: Richard N
authors.initials: RN
authors.lastname: Schlussel
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burk
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Francesco
authors.initials: F
authors.lastname: Scolari
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
authors.forename: Kenneth
authors.initials: K
authors.lastname: Glassberg
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D007558:Italy; D007585:Jews / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D040641:Quantitative Trait Loci / Q000235:genetics; D014481:United States; D014718:Vesico-Ureteral Reflux / Q000208:ethnology / Q000235:genetics*; D044465:White People / Q000235:genetics