RT Journal Article
SR Electronic
T1 Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux
JF Journal of the American Society of Nephrology
JO J. Am. Soc. Nephrol.
FD American Society of Nephrology
SP ASN.2020050681
DO 10.1681/ASN.2020050681
A1 Verbitsky, Miguel
A1 Krithivasan, Priya
A1 Batourina, Ekaterina
A1 Khan, Atlas
A1 Graham, Sarah E.
A1 Marasà, Maddalena
A1 Kim, Hyunwoo
A1 Lim, Tze Y.
A1 Weng, Patricia L.
A1 Sánchez-Rodríguez, Elena
A1 Mitrotti, Adele
A1 Ahram, Dina F.
A1 Zanoni, Francesca
A1 Fasel, David A.
A1 Westland, Rik
A1 Sampson, Matthew G.
A1 Zhang, Jun Y.
A1 Bodria, Monica
A1 Kil, Byum Hee
A1 Shril, Shirlee
A1 Gesualdo, Loreto
A1 Torri, Fabio
A1 Scolari, Francesco
A1 Izzi, Claudia
A1 van Wijk, Joanna A.E.
A1 Saraga, Marijan
A1 Santoro, Domenico
A1 Conti, Giovanni
A1 Barton, David E.
A1 Dobson, Mark G.
A1 Puri, Prem
A1 Furth, Susan L.
A1 Warady, Bradley A.
A1 Pisani, Isabella
A1 Fiaccadori, Enrico
A1 Allegri, Landino
A1 Degl'Innocenti, Maria Ludovica
A1 Piaggio, Giorgio
A1 Alam, Shumyle
A1 Gigante, Maddalena
A1 Zaza, Gianluigi
A1 Esposito, Pasquale
A1 Lin, Fangming
A1 Simões-e-Silva, Ana Cristina
A1 Brodkiewicz, Andrzej
A1 Drozdz, Dorota
A1 Zachwieja, Katarzyna
A1 Miklaszewska, Monika
A1 Szczepanska, Maria
A1 Adamczyk, Piotr
A1 Tkaczyk, Marcin
A1 Tomczyk, Daria
A1 Sikora, Przemyslaw
A1 Mizerska-Wasiak, Malgorzata
A1 Krzemien, Grazyna
A1 Szmigielska, Agnieszka
A1 Zaniew, Marcin
A1 Lozanovski, Vladimir J.
A1 Gucev, Zoran
A1 Ionita-Laza, Iuliana
A1 Stanaway, Ian B.
A1 Crosslin, David R.
A1 Wong, Craig S.
A1 Hildebrandt, Friedhelm
A1 Barasch, Jonathan
A1 Kenny, Eimear E.
A1 Loos, Ruth J.F.
A1 Levy, Brynn
A1 Ghiggeri, Gian Marco
A1 Hakonarson, Hakon
A1 Latos-Bieleńska, Anna
A1 Materna-Kiryluk, Anna
A1 Darlow, John M.
A1 Tasic, Velibor
A1 Willer, Cristen
A1 Kiryluk, Krzysztof
A1 Sanna-Cherchi, Simone
A1 Mendelsohn, Cathy L.
A1 Gharavi, Ali G.
YR 2021
UL http://jasn.asnjournals.org/content/early/2021/02/16/ASN.2020050681.abstract
AB Vesicoureteral reflux (VUR) is associated with progressive kidney disease. Familial aggregation supports a hereditary basis; however, its genetic architecture remains to be elucidated. The largest VUR copy number variant analysis and genome-wide association study to date accounts for multiple modes of inheritance and sex-specific effects in VUR, identifying three study-wide significant and five suggestive loci with large effects, containing canonical developmental genes including WDPCP and WNT5A. Results of experiments in mice support novel roles of Wnt5a in urogenital development. Altogether, 6% of patients carried high-risk genotypes. These findings have important implications for VUR screening.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 A 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.Results Altogether, 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.Conclusions These 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.