Miguel Verbitsky1, Priya Krithivasan1, Ekaterina Batourina2, Atlas Khan1, Sarah E Graham3, Maddalena Marasà1, Hyunwoo Kim2, Tze Y Lim1, Patricia L Weng4, Elena Sánchez-Rodríguez1, Adele Mitrotti1,5, Dina F Ahram1, Francesca Zanoni1, David A Fasel1, Rik Westland1,6, Matthew G Sampson7, Jun Y Zhang1, Monica Bodria8, Byum Hee Kil1, Shirlee Shril9, Loreto Gesualdo5, Fabio Torri10, Francesco Scolari11, Claudia Izzi12, Joanna A E van Wijk6, Marijan Saraga13,14, Domenico Santoro15, Giovanni Conti16, David E Barton17,18, Mark G Dobson18,19, Prem Puri19,20, Susan L Furth21, Bradley A Warady22, Isabella Pisani23, Enrico Fiaccadori23, Landino Allegri23, Maria Ludovica Degl'Innocenti8, Giorgio Piaggio8, Shumyle Alam24, Maddalena Gigante5, Gianluigi Zaza25, Pasquale Esposito26, Fangming Lin27, Ana Cristina Simões-E-Silva28, Andrzej Brodkiewicz29, Dorota Drozdz30, Katarzyna Zachwieja30, Monika Miklaszewska30, Maria Szczepanska31, Piotr Adamczyk31, Marcin Tkaczyk32, Daria Tomczyk32, Przemyslaw Sikora33, Malgorzata Mizerska-Wasiak34, Grazyna Krzemien34, Agnieszka Szmigielska34, Marcin Zaniew35, Vladimir J Lozanovski36,37, Zoran Gucev37, Iuliana Ionita-Laza38, Ian B Stanaway39, David R Crosslin39, Craig S Wong40, Friedhelm Hildebrandt9, Jonathan Barasch1,2, Eimear E Kenny41,42,43, Ruth J F Loos44, Brynn Levy45, Gian Marco Ghiggeri8, Hakon Hakonarson46, Anna Latos-Bieleńska47, Anna Materna-Kiryluk47, John M Darlow18,19, Velibor Tasic37, Cristen Willer3,48,49, Krzysztof Kiryluk1, Simone Sanna-Cherchi1, Cathy L Mendelsohn2, Ali G Gharavi50. 1. Division of Nephrology, Department of Medicine, Columbia University, New York, New York. 2. Department of Urology, Columbia University, New York, New York. 3. Department of Internal Medicine, Cardiology, University of Michigan, Ann Arbor, Michigan. 4. Department of Pediatric Nephrology, University of California, Los Angeles Medical Center and University of California, Los Angeles Medical Center-Santa Monica, Los Angeles, California. 5. Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. 6. Department of Pediatric Nephrology, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands. 7. Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts. 8. Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy. 9. Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. 10. Department of Pediatric Surgery, Spedali Civili Children's Hospital of Brescia, Brescia, Italy. 11. Chair and Division of Nephrology, University and Spedali Civili Hospital, Brescia, Italy. 12. Division of Nephrology and Department of Obstetrics and Gynecology, ASST Spedali Civili of Brescia, Brescia, Italy. 13. Department of Pediatrics, University Hospital of Split, Split, Croatia. 14. School of Medicine, University of Split, Split, Croatia. 15. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. 16. Department of Pediatric Nephrology, Azienda Ospedaliera Universitaria "G. Martino," Messina, Italy. 17. University College Dublin School of Medicine, Our Lady's Children's Hospital Crumlin, Dublin, Ireland. 18. Department of Clinical Genetics, Our Lady's Children's Hospital Crumlin, Dublin, Ireland. 19. National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland. 20. Department of Pediatric Surgery, Beacon Hospital, University College Dublin, Dublin, Ireland. 21. Division of Nephrology, Departments of Pediatrics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 22. Division of Nephrology, Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Children's Mercy Kansas City, Kansas City, Missouri. 23. Nephrology Unit, Parma University Hospital and Department of Medicine and Surgery, Parma University Medical School, Parma, Italy. 24. Department of Pediatric Urology, Columbia University College of Physicians and Surgeons, New York, New York. 25. Renal and Dialysis Unit, Department of Medicine, School of Medicine, University of Verona, Verona, Italy. 26. Department of Internal Medicine, Nephrology, Dialysis and Transplantation Clinics, Genoa University and IRCCS Policlinico San Martino, Genova, Italy. 27. Division of Pediatric Nephrology, Department of Pediatrics, Columbia University, New York, New York. 28. Department of Pediatrics, Unit of Pediatric Nephrology, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil. 29. Department of Pediatrics, Child Nephrology, Dialysotheraphy and Management of Acute Poisoning, Pomeranian Medical University, Szczecin, Poland. 30. Department of Pediatric Nephrology and Hypertension, Jagiellonian University Medical College, Krakow, Poland. 31. Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland. 32. Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland. 33. Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland. 34. Department of Pediatrics and Nephrology, Medical University of Warsaw, Poland. 35. Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland. 36. University Clinic for General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. 37. University Children's Hospital, Medical Faculty of Skopje, Skopje, Macedonia. 38. Department of Biostatistics, Columbia University, New York, New York. 39. Department of Biomedical Informatics and Medical Education, University of Washington School of Medicine, Seattle, Washington. 40. Division of Pediatric Nephrology, University of New Mexico Children's Hospital, Albuquerque, New Mexico. 41. Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York. 42. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 43. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. 44. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York. 45. Department of Pathology and Cell Biology, Columbia University, New York, New York. 46. Center for Applied Genomics, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 47. Department of Medical Genetics, Poznan University of Medical Sciences, and NZOZ Center for Medical Genetics GENESIS, Poznan, Poland. 48. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan. 49. Department of Computational Medicine and Bioinformatics, Ann Arbor, Michigan. 50. Division of Nephrology, Department of Medicine, Columbia University, New York, New York ag2239@cumc.columbia.edu clm20@cumc.columbia.edu.
Abstract
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.
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.
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Authors: Chen-Han Wilfred Wu; Tze Y Lim; Chunyan Wang; Steve Seltzsam; Bixia Zheng; Luca Schierbaum; Sophia Schneider; Nina Mann; Dervla M Connaughton; Makiko Nakayama; Amelie T van der Ven; Rufeng Dai; Caroline M Kolvenbach; Franziska Kause; Isabel Ottlewski; Natasa Stajic; Neveen A Soliman; Jameela A Kari; Sherif El Desoky; Hanan M Fathy; Danko Milosevic; Daniel Turudic; Muna Al Saffar; Hazem S Awad; Loai A Eid; Aravind Ramanathan; Prabha Senguttuvan; Shrikant M Mane; Richard S Lee; Stuart B Bauer; Weining Lu; Alina C Hilger; Velibor Tasic; Shirlee Shril; Simone Sanna-Cherchi; Friedhelm Hildebrandt Journal: Eur Urol Open Sci Date: 2022-09-01