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

Mar 1, 2021

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

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.
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.
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; =6.35×10) 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 ( and ). In particular, 3.3% of VUR patients were homozygous for an intronic variant in (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; =1.86×10). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis.
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.

Copyright © 2021 by the American Society of Nephrology.

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Miguel Verbitsky

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Priya Krithivasan

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Ekaterina Batourina

Department of Urology, Columbia University, New York, New York.

Atlas Khan

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Sarah E Graham

Department of Internal Medicine, Cardiology, University of Michigan, Ann Arbor, Michigan.

Maddalena Marasà

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Hyunwoo Kim

Department of Urology, Columbia University, New York, New York.

Tze Y Lim

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Patricia L Weng

Department of Pediatric Nephrology, University of California, Los Angeles Medical Center and University of California, Los Angeles Medical Center-Santa Monica, Los Angeles, California.

Elena Sánchez-Rodríguez

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Adele Mitrotti

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Dina F Ahram

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Francesca Zanoni

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

David A Fasel

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Rik Westland

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Department of Pediatric Nephrology, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands.

Matthew G Sampson

Division of Nephrology, Boston Children’s Hospital, Boston, Massachusetts.

Jun Y Zhang

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Monica Bodria

Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy.

Byum Hee Kil

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Shirlee Shril

Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts.

Loreto Gesualdo

Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Fabio Torri

Department of Pediatric Surgery, Spedali Civili Children’s Hospital of Brescia, Brescia, Italy.

Francesco Scolari

Chair and Division of Nephrology, University and Spedali Civili Hospital, Brescia, Italy.

Claudia Izzi

Division of Nephrology and Department of Obstetrics and Gynecology, ASST Spedali Civili of Brescia, Brescia, Italy.

Joanna A E van Wijk

Department of Pediatric Nephrology, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands.

Marijan Saraga

Department of Pediatrics, University Hospital of Split, Split, Croatia.

School of Medicine, University of Split, Split, Croatia.

Domenico Santoro

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Giovanni Conti

Department of Pediatric Nephrology, Azienda Ospedaliera Universitaria “G. Martino,” Messina, Italy.

David E Barton

University College Dublin School of Medicine, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland.

Department of Clinical Genetics, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland.

Mark G Dobson

Department of Clinical Genetics, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland.

National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland.

Prem Puri

National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland.

Department of Pediatric Surgery, Beacon Hospital, University College Dublin, Dublin, Ireland.

Susan L Furth

Division of Nephrology, Departments of Pediatrics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Bradley A Warady

Division of Nephrology, Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Children’s Mercy Kansas City, Kansas City, Missouri.

Isabella Pisani

Nephrology Unit, Parma University Hospital and Department of Medicine and Surgery, Parma University Medical School, Parma, Italy.

Enrico Fiaccadori

Nephrology Unit, Parma University Hospital and Department of Medicine and Surgery, Parma University Medical School, Parma, Italy.

Landino Allegri

Nephrology Unit, Parma University Hospital and Department of Medicine and Surgery, Parma University Medical School, Parma, Italy.

Maria Ludovica Degl’Innocenti

Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy.

Giorgio Piaggio

Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy.

Shumyle Alam

Department of Pediatric Urology, Columbia University College of Physicians and Surgeons, New York, New York.

Maddalena Gigante

Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Gianluigi Zaza

Renal and Dialysis Unit, Department of Medicine, School of Medicine, University of Verona, Verona, Italy.

Pasquale Esposito

Department of Internal Medicine, Nephrology, Dialysis and Transplantation Clinics, Genoa University and IRCCS Policlinico San Martino, Genova, Italy.

Fangming Lin

Division of Pediatric Nephrology, Department of Pediatrics, Columbia University, New York, New York.

Ana Cristina Simões-E-Silva

Department of Pediatrics, Unit of Pediatric Nephrology, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Andrzej Brodkiewicz

Department of Pediatrics, Child Nephrology, Dialysotheraphy and Management of Acute Poisoning, Pomeranian Medical University, Szczecin, Poland.

Dorota Drozdz

Department of Pediatric Nephrology and Hypertension, Jagiellonian University Medical College, Krakow, Poland.

Katarzyna Zachwieja

Department of Pediatric Nephrology and Hypertension, Jagiellonian University Medical College, Krakow, Poland.

Monika Miklaszewska

Department of Pediatric Nephrology and Hypertension, Jagiellonian University Medical College, Krakow, Poland.

Maria Szczepanska

Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland.

Piotr Adamczyk

Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland.

Marcin Tkaczyk

Department of Pediatrics, Immunology and Nephrology, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland.

Daria Tomczyk

Department of Pediatrics, Immunology and Nephrology, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland.

Przemyslaw Sikora

Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland.

Malgorzata Mizerska-Wasiak

Department of Pediatrics and Nephrology, Medical University of Warsaw, Poland.

Grazyna Krzemien

Department of Pediatrics and Nephrology, Medical University of Warsaw, Poland.

Agnieszka Szmigielska

Department of Pediatrics and Nephrology, Medical University of Warsaw, Poland.

Marcin Zaniew

Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland.

Vladimir J Lozanovski

University Clinic for General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

University Children’s Hospital, Medical Faculty of Skopje, Skopje, Macedonia.

Zoran Gucev

University Children’s Hospital, Medical Faculty of Skopje, Skopje, Macedonia.

Iuliana Ionita-Laza

Department of Biostatistics, Columbia University, New York, New York.

Ian B Stanaway

Department of Biomedical Informatics and Medical Education, University of Washington School of Medicine, Seattle, Washington.

David R Crosslin

Department of Biomedical Informatics and Medical Education, University of Washington School of Medicine, Seattle, Washington.

Craig S Wong

Division of Pediatric Nephrology, University of New Mexico Children’s Hospital, Albuquerque, New Mexico.

Friedhelm Hildebrandt

Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts.

Jonathan Barasch

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Department of Urology, Columbia University, New York, New York.

Eimear E Kenny

Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

Ruth J F Loos

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York.

Brynn Levy

Department of Pathology and Cell Biology, Columbia University, New York, New York.

Gian Marco Ghiggeri

Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa, Italy.

Hakon Hakonarson

Center for Applied Genomics, The Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Anna Latos-Bieleńska

Department of Medical Genetics, Poznan University of Medical Sciences, and NZOZ Center for Medical Genetics GENESIS, Poznan, Poland.

Anna Materna-Kiryluk

Department of Medical Genetics, Poznan University of Medical Sciences, and NZOZ Center for Medical Genetics GENESIS, Poznan, Poland.

John M Darlow

Department of Clinical Genetics, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland.

National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland.

Velibor Tasic

University Children’s Hospital, Medical Faculty of Skopje, Skopje, Macedonia.

Cristen Willer

Department of Internal Medicine, Cardiology, University of Michigan, Ann Arbor, Michigan.

Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.

Department of Computational Medicine and Bioinformatics, Ann Arbor, Michigan.

Krzysztof Kiryluk

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Simone Sanna-Cherchi

Division of Nephrology, Department of Medicine, Columbia University, New York, New York.

Cathy L Mendelsohn

Department of Urology, Columbia University, New York, New York.

Ali G Gharavi

Division of Nephrology, Department of Medicine, Columbia University, New York, New York ag2239@cumc.columbia.edu clm20@cumc.columbia.edu.

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

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About The Expert

References