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

Autori
Verbitsky, Miguel ; Krithivasan, Priya ; Batourina, Ekaterina ; Khan, Atlas ; Graham, Sarah E. ; Marasà, Maddalena ; Kim, Hyunwoo ; Lim, Tze Y. ; Weng, Patricia L. ; Sánchez-Rodríguez, Elena ; Mitrotti, Adele ; Ahram, Dina F. ; Zanoni, Francesca ; Fasel, David A. ; Westland, Rik ; Sampson, Matthew G. ; Zhang, Jun Y. ; Bodria, Monica ; Kil, Byum Hee ; Shril, Shirlee ; Gesualdo, Loreto ; Torri, Fabio ; Scolari, Francesco ; Izzi, Claudia ; van Wijk, Joanna A.E. ; Saraga, Marijan ; Santoro, Domenico ; Conti, Giovanni ; Barton, David E. ; Dobson, Mark G. ; Puri, Prem ; Furth, Susan L. ; Warady, Bradley A. ; Pisani, Isabella ; Fiaccadori, Enrico ; Allegri, Landino ; Degl'Innocenti, Maria Ludovica ; Piaggio, Giorgio ; Alam, Shumyle ; Gigante, Maddalena ; Zaza, Gianluigi ; Esposito, Pasquale ; Lin, Fangming ; Simões-e-Silva, Ana Cristina ; Brodkiewicz, Andrzej ; Drozdz, Dorota ; Zachwieja, Katarzyna ; Miklaszewska, Monika ; Szczepanska, Maria ; Adamczyk, Piotr ; Tkaczyk, Marcin ; Tomczyk, Daria ; Sikora, Przemyslaw ; Mizerska- Wasiak, Malgorzata ; Krzemien, Grazyna ; Szmigielska, Agnieszka ; Zaniew, Marcin ; Lozanovski, Vladimir J. ; Gucev, Zoran ; Ionita- Laza, Iuliana ; Stanaway, Ian B. ; Crosslin, David R. ; Wong, Craig S. ; Hildebrandt, Friedhelm ; Barasch, Jonathan ; Kenny, Eimear E. ; Loos, Ruth J.F. ; Levy, Brynn ; Ghiggeri, Gian Marco ; Hakonarson, Hakon ; Latos-Bieleńska, Anna ; Materna-Kiryluk, Anna ; Darlow, John M. ; Tasic, Velibor ; Willer, Cristen ; Kiryluk, Krzysztof ; Sanna-Cherchi, Simone ; Mendelsohn, Cathy L. ; Gharavi, Ali G.

Izvornik
Journal of the American Society of Nephrology (1046-6673) 32 (2021), 4; 805-820

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
vesico-ureteral reflux ; human genetics ; genetics and development ; pediatric nephrology

Sažetak
Background: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and amajor 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=6.35x10(-8)) TheGWAS identified three studywide 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, andWNT5A). 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=1.86x10(-9)). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis ofWnt5amutant mice confirmedthe roleofWnt5a signaling inbladder and uretericmorphogenesis. 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.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

POVEZANOST RADA