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Copy number variant analysis and genome-wide association study identify loci with large effect for vesicoureteral reflux

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) dis...

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Hauptverfasser: Verbitsky, Miguel (VerfasserIn) , Krithivasan, Priya (VerfasserIn) , Batourina, Ekaterina (VerfasserIn) , Khan, Atlas (VerfasserIn) , Graham, Sarah E. (VerfasserIn) , Marasà, Maddalena (VerfasserIn) , Kim, Hyunwoo (VerfasserIn) , Lim, Tze Y. (VerfasserIn) , Weng, Patricia L. (VerfasserIn) , Sánchez-Rodríguez, Elena (VerfasserIn) , Mitrotti, Adele (VerfasserIn) , Ahram, Dina F. (VerfasserIn) , Zanoni, Francesca (VerfasserIn) , Fasel, David A. (VerfasserIn) , Westland, Rik (VerfasserIn) , Sampson, Matthew G. (VerfasserIn) , Zhang, Jun Y. (VerfasserIn) , Bodria, Monica (VerfasserIn) , Kil, Byum Hee (VerfasserIn) , Shril, Shirlee (VerfasserIn) , Gesualdo, Loreto (VerfasserIn) , Torri, Fabio (VerfasserIn) , Scolari, Francesco (VerfasserIn) , Izzi, Claudia (VerfasserIn) , Wijk, Joanna A. E. van (VerfasserIn) , Saraga, Marijan (VerfasserIn) , Santoro, Domenico (VerfasserIn) , Conti, Giovanni (VerfasserIn) , Barton, David E. (VerfasserIn) , Dobson, Mark G. (VerfasserIn) , Puri, Prem (VerfasserIn) , Furth, Susan L. (VerfasserIn) , Warady, Bradley A. (VerfasserIn) , Pisani, Isabella (VerfasserIn) , Fiaccadori, Enrico (VerfasserIn) , Allegri, Landino (VerfasserIn) , Degl'Innocenti, Maria Ludovica (VerfasserIn) , Piaggio, Giorgio (VerfasserIn) , Alam, Shumyle (VerfasserIn) , Gigante, Maddalena (VerfasserIn) , Zaza, Gianluigi (VerfasserIn) , Esposito, Pasquale (VerfasserIn) , Lin, Fangming (VerfasserIn) , Simões-e-Silva, Ana Cristina (VerfasserIn) , Brodkiewicz, Andrzej (VerfasserIn) , Drozdz, Dorota (VerfasserIn) , Zachwieja, Katarzyna (VerfasserIn) , Miklaszewska, Monika (VerfasserIn) , Szczepanska, Maria (VerfasserIn) , Adamczyk, Piotr (VerfasserIn) , Tkaczyk, Marcin (VerfasserIn) , Tomczyk, Daria (VerfasserIn) , Sikora, Przemyslaw (VerfasserIn) , Mizerska-Wasiak, Malgorzata (VerfasserIn) , Krzemien, Grazyna (VerfasserIn) , Szmigielska, Agnieszka (VerfasserIn) , Zaniew, Marcin (VerfasserIn) , Lozanovski, Vladimir J. (VerfasserIn) , Gucev, Zoran (VerfasserIn) , Ionita-Laza, Iuliana (VerfasserIn) , Stanaway, Ian B. (VerfasserIn) , Crosslin, David R. (VerfasserIn) , Wong, Craig S. (VerfasserIn) , Hildebrandt, Friedhelm (VerfasserIn) , Barasch, Jonathan (VerfasserIn) , Kenny, Eimear E. (VerfasserIn) , Loos, Ruth J. F. (VerfasserIn) , Levy, Brynn (VerfasserIn) , Ghiggeri, Gian Marco (VerfasserIn) , Hakonarson, Hakon (VerfasserIn) , Latos-Bieleńska, Anna (VerfasserIn) , Materna-Kiryluk, Anna (VerfasserIn) , Darlow, John M. (VerfasserIn) , Tasic, Velibor (VerfasserIn) , Willer, Cristen (VerfasserIn) , Kiryluk, Krzysztof (VerfasserIn) , Sanna-Cherchi, Simone (VerfasserIn) , Mendelsohn, Cathy L. (VerfasserIn) , Gharavi, Ali G. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: March 31, 2021
In: Journal of the American Society of Nephrology
Year: 2021, Jahrgang: 32, Heft: 4, Pages: 805-820
ISSN:1533-3450
DOI:10.1681/ASN.2020050681
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1681/ASN.2020050681
Verlag, lizenzpflichtig, Volltext: https://jasn.asnjournals.org/content/32/4/805
Volltext
Verfasserangaben: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, and Ali G. Gharavi

MARC

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245 1 0 |a Copy number variant analysis and genome-wide association study identify loci with large effect for vesicoureteral reflux  |c 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, and Ali G. Gharavi 
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520 |a 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. 
650 4 |a genetics and development 
650 4 |a human genetics 
650 4 |a pediatric nephrology 
650 4 |a vesico-ureteral reflux 
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700 1 |a Batourina, Ekaterina  |e VerfasserIn  |4 aut 
700 1 |a Khan, Atlas  |e VerfasserIn  |4 aut 
700 1 |a Graham, Sarah E.  |e VerfasserIn  |4 aut 
700 1 |a Marasà, Maddalena  |e VerfasserIn  |4 aut 
700 1 |a Kim, Hyunwoo  |e VerfasserIn  |4 aut 
700 1 |a Lim, Tze Y.  |e VerfasserIn  |4 aut 
700 1 |a Weng, Patricia L.  |e VerfasserIn  |4 aut 
700 1 |a Sánchez-Rodríguez, Elena  |e VerfasserIn  |4 aut 
700 1 |a Mitrotti, Adele  |e VerfasserIn  |4 aut 
700 1 |a Ahram, Dina F.  |e VerfasserIn  |4 aut 
700 1 |a Zanoni, Francesca  |e VerfasserIn  |4 aut 
700 1 |a Fasel, David A.  |e VerfasserIn  |4 aut 
700 1 |a Westland, Rik  |e VerfasserIn  |4 aut 
700 1 |a Sampson, Matthew G.  |e VerfasserIn  |4 aut 
700 1 |a Zhang, Jun Y.  |e VerfasserIn  |4 aut 
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700 1 |a Torri, Fabio  |e VerfasserIn  |4 aut 
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700 1 |a Izzi, Claudia  |e VerfasserIn  |4 aut 
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700 1 |a Alam, Shumyle  |e VerfasserIn  |4 aut 
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700 1 |a Zaza, Gianluigi  |e VerfasserIn  |4 aut 
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SRT |a VERBITSKYMCOPYNUMBER3120 

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