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

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

doi:10.1681/ASN.2020050681

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

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 ShrilLoreto 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

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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.

Original language	English
Pages (from-to)	805-820
Number of pages	16
Journal	Journal of the American Society of Nephrology : JASN
Volume	32
Issue number	4
DOIs	https://doi.org/10.1681/ASN.2020050681
State	Published - 1 Apr 2021

Keywords

genetics and development
human genetics
pediatric nephrology
vesico-ureteral reflux

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10.1681/ASN.2020050681

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Verbitsky, M., Krithivasan, P., Batourina, E., Khan, A., Graham, S. E., Marasà, M., Kim, H., Lim, T. Y., Weng, P. L., Sánchez-Rodríguez, E., Mitrotti, A., Ahram, D. F., Zanoni, F., Fasel, D. A., Westland, R., Sampson, M. G., Zhang, J. Y., Bodria, M., Kil, B. H., ... Gharavi, A. G. (2021). Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux. Journal of the American Society of Nephrology : JASN, 32(4), 805-820. https://doi.org/10.1681/ASN.2020050681

@article{7defd9a36e7b4fbd84b89740f6a6aaa4,

title = "Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux",

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.",

keywords = "genetics and development, human genetics, pediatric nephrology, vesico-ureteral reflux",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2021 by the American Society of Nephrology.",

year = "2021",

month = apr,

day = "1",

doi = "10.1681/ASN.2020050681",

language = "English",

volume = "32",

pages = "805--820",

journal = "Journal of the American Society of Nephrology : JASN",

issn = "1046-6673",

publisher = "Wolters Kluwer Health",

number = "4",

}

Verbitsky, M, Krithivasan, P, Batourina, E, Khan, A, Graham, SE, Marasà, M, Kim, H, Lim, TY, Weng, PL, Sánchez-Rodríguez, E, Mitrotti, A, Ahram, DF, Zanoni, F, Fasel, DA, Westland, R, Sampson, MG, Zhang, JY, Bodria, M, Kil, BH, Shril, S, Gesualdo, L, Torri, F, Scolari, F, Izzi, C, van Wijk, JAE, Saraga, M, Santoro, D, Conti, G, Barton, DE, Dobson, MG, Puri, P, Furth, SL, Warady, BA, Pisani, I, Fiaccadori, E, Allegri, L, Degl'Innocenti, ML, Piaggio, G, Alam, S, Gigante, M, Zaza, G, Esposito, P, Lin, F, Simões-E-Silva, AC, Brodkiewicz, A, Drozdz, D, Zachwieja, K, Miklaszewska, M, Szczepanska, M, Adamczyk, P, Tkaczyk, M, Tomczyk, D, Sikora, P, Mizerska-Wasiak, M, Krzemien, G, Szmigielska, A, Zaniew, M, Lozanovski, VJ, Gucev, Z, Ionita-Laza, I, Stanaway, IB, Crosslin, DR, Wong, CS, Hildebrandt, F, Barasch, J, Kenny, EE, Loos, RJF, Levy, B, Ghiggeri, GM, Hakonarson, H, Latos-Bieleńska, A, Materna-Kiryluk, A, Darlow, JM, Tasic, V, Willer, C, Kiryluk, K, Sanna-Cherchi, S, Mendelsohn, CL & Gharavi, AG 2021, 'Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux', Journal of the American Society of Nephrology : JASN, vol. 32, no. 4, pp. 805-820. https://doi.org/10.1681/ASN.2020050681

TY - JOUR

T1 - Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux

AU - Verbitsky, Miguel

AU - Krithivasan, Priya

AU - Batourina, Ekaterina

AU - Khan, Atlas

AU - Graham, Sarah E.

AU - Marasà, Maddalena

AU - Kim, Hyunwoo

AU - Lim, Tze Y.

AU - Weng, Patricia L.

AU - Sánchez-Rodríguez, Elena

AU - Mitrotti, Adele

AU - Ahram, Dina F.

AU - Zanoni, Francesca

AU - Fasel, David A.

AU - Westland, Rik

AU - Sampson, Matthew G.

AU - Zhang, Jun Y.

AU - Bodria, Monica

AU - Kil, Byum Hee

AU - Shril, Shirlee

AU - Gesualdo, Loreto

AU - Torri, Fabio

AU - Scolari, Francesco

AU - Izzi, Claudia

AU - van Wijk, Joanna A.E.

AU - Saraga, Marijan

AU - Santoro, Domenico

AU - Conti, Giovanni

AU - Barton, David E.

AU - Dobson, Mark G.

AU - Puri, Prem

AU - Furth, Susan L.

AU - Warady, Bradley A.

AU - Pisani, Isabella

AU - Fiaccadori, Enrico

AU - Allegri, Landino

AU - Degl'Innocenti, Maria Ludovica

AU - Piaggio, Giorgio

AU - Alam, Shumyle

AU - Gigante, Maddalena

AU - Zaza, Gianluigi

AU - Esposito, Pasquale

AU - Lin, Fangming

AU - Simões-E-Silva, Ana Cristina

AU - Brodkiewicz, Andrzej

AU - Drozdz, Dorota

AU - Zachwieja, Katarzyna

AU - Miklaszewska, Monika

AU - Szczepanska, Maria

AU - Adamczyk, Piotr

AU - Tkaczyk, Marcin

AU - Tomczyk, Daria

AU - Sikora, Przemyslaw

AU - Mizerska-Wasiak, Malgorzata

AU - Krzemien, Grazyna

AU - Szmigielska, Agnieszka

AU - Zaniew, Marcin

AU - Lozanovski, Vladimir J.

AU - Gucev, Zoran

AU - Ionita-Laza, Iuliana

AU - Stanaway, Ian B.

AU - Crosslin, David R.

AU - Wong, Craig S.

AU - Hildebrandt, Friedhelm

AU - Barasch, Jonathan

AU - Kenny, Eimear E.

AU - Loos, Ruth J.F.

AU - Levy, Brynn

AU - Ghiggeri, Gian Marco

AU - Hakonarson, Hakon

AU - Latos-Bieleńska, Anna

AU - Materna-Kiryluk, Anna

AU - Darlow, John M.

AU - Tasic, Velibor

AU - Willer, Cristen

AU - Kiryluk, Krzysztof

AU - Sanna-Cherchi, Simone

AU - Mendelsohn, Cathy L.

AU - Gharavi, Ali G.

PY - 2021/4/1

Y1 - 2021/4/1

N2 - 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.

AB - 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.

KW - genetics and development

KW - human genetics

KW - pediatric nephrology

KW - vesico-ureteral reflux

UR - http://www.scopus.com/inward/record.url?scp=85123352326&partnerID=8YFLogxK

U2 - 10.1681/ASN.2020050681

DO - 10.1681/ASN.2020050681

M3 - Article

C2 - 33597122

AN - SCOPUS:85123352326

SN - 1046-6673

VL - 32

SP - 805

EP - 820

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

IS - 4

ER -

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

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