Genome-wide association study of kidney function decline in individuals of European descent

Mathias Gorski; Adrienne Tin; Maija Garnaas; Gearoid M. McMahon; Audrey Y. Chu; Bamidele O. Tayo; Cristian Pattaro; Alexander Teumer; Daniel I. Chasman; John Chalmers; Pavel Hamet; Johanne Tremblay; Marc Woodward; Thor Aspelund; Gudny Eiriksdottir; Vilmundur Gudnason; Tamara B. Harris; Lenore J. Launer; Albert V. Smith; Braxton D. Mitchell; Jeffrey R. O'Connell; Alan R. Shuldiner; Josef Coresh; Man Li; Paul Freudenberger; Edith Hofer; Helena Schmidt; Reinhold Schmidt; Elizabeth G. Holliday; Paul Mitchell; Jie Jin Wang; Ian H. De Boer; Guo Li; David S. Siscovick; Zoltan Kutalik; Tanguy Corre; Peter Vollenweider; Gérard Waeber; Jayanta Gupta; Peter A. Kanetsky; Shih Jen Hwang; Matthias Olden; Qiong Yang; Mariza De Andrade; Elizabeth J. Atkinson; Sharon L.R. Kardia; Stephen T. Turner; Jeanette M. Stafford; Jingzhong Ding; Yongmei Liu; Cristina Barlassina; Daniele Cusi; Erika Salvi; Jan A. Staessen; Paul M. Ridker; Harald Grallert; Christa Meisinger; Martina Müller-Nurasyid; Bernhard K. Krämer; Holly Kramer; Sylvia E. Rosas; Ilja M. Nolte; Brenda W. Penninx; Harold Snieder; M. Fabiola Del Greco; Andre Franke; Ute Nöthlings; Wolfgang Lieb; Stephan J.L. Bakker; Ron T. Gansevoort; Pim Van Der Harst; Abbas Dehghan; Oscar H. Franco; Albert Hofman; Fernando Rivadeneira; Sanaz Sedaghat; André G. Uitterlinden; Stefan Coassin; Margot Haun; Barbara Kollerits; Florian Kronenberg; Bernhard Paulweber; Nicole Aumann; Karlhans Endlich; Mike Pietzner; Uwe Völker; Rainer Rettig; Vincent Chouraki; Catherine Helmer; Jean Charles Lambert; Marie Metzger; Benedicte Stengel; Terho Lehtimäki; Leo Pekka Lyytikäinen; Olli Raitakari; Andrew Johnson; Afshin Parsa; Murielle Bochud; Iris M. Heid; Wolfram Goessling; Anna Köttgen; W. H.Linda Kao; Caroline S. Fox; Carsten A. Böger

doi:10.1038/ki.2014.361

Genome-wide association study of kidney function decline in individuals of European descent

Mathias Gorski, Adrienne Tin, Maija Garnaas, Gearoid M. McMahon, Audrey Y. Chu, Bamidele O. Tayo, Cristian Pattaro, Alexander Teumer, Daniel I. Chasman, John Chalmers, Pavel Hamet, Johanne Tremblay, Marc Woodward, Thor Aspelund, Gudny Eiriksdottir, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Braxton D. MitchellJeffrey R. O'Connell, Alan R. Shuldiner, Josef Coresh, Man Li, Paul Freudenberger, Edith Hofer, Helena Schmidt, Reinhold Schmidt, Elizabeth G. Holliday, Paul Mitchell, Jie Jin Wang, Ian H. De Boer, Guo Li, David S. Siscovick, Zoltan Kutalik, Tanguy Corre, Peter Vollenweider, Gérard Waeber, Jayanta Gupta, Peter A. Kanetsky, Shih Jen Hwang, Matthias Olden, Qiong Yang, Mariza De Andrade, Elizabeth J. Atkinson, Sharon L.R. Kardia, Stephen T. Turner, Jeanette M. Stafford, Jingzhong Ding, Yongmei Liu, Cristina Barlassina, Daniele Cusi, Erika Salvi, Jan A. Staessen, Paul M. Ridker, Harald Grallert, Christa Meisinger, Martina Müller-Nurasyid, Bernhard K. Krämer, Holly Kramer, Sylvia E. Rosas, Ilja M. Nolte, Brenda W. Penninx, Harold Snieder, M. Fabiola Del Greco, Andre Franke, Ute Nöthlings, Wolfgang Lieb, Stephan J.L. Bakker, Ron T. Gansevoort, Pim Van Der Harst, Abbas Dehghan, Oscar H. Franco, Albert Hofman, Fernando Rivadeneira, Sanaz Sedaghat, André G. Uitterlinden, Stefan Coassin, Margot Haun, Barbara Kollerits, Florian Kronenberg, Bernhard Paulweber, Nicole Aumann, Karlhans Endlich, Mike Pietzner, Uwe Völker, Rainer Rettig, Vincent Chouraki, Catherine Helmer, Jean Charles Lambert, Marie Metzger, Benedicte Stengel, Terho Lehtimäki, Leo Pekka Lyytikäinen, Olli Raitakari, Andrew Johnson, Afshin Parsa, Murielle Bochud, Iris M. Heid, Wolfram Goessling, Anna Köttgen, W. H.Linda Kao, Caroline S. Fox, Carsten A. Böger

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

Abstract

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m 2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

Original language	English (US)
Pages (from-to)	1017-1029
Number of pages	13
Journal	Kidney international
Volume	87
Issue number	5
DOIs	https://doi.org/10.1038/ki.2014.361
State	Published - May 11 2015

Keywords

chronic kidney disease
genome-wide association study
kidney development
kidney function decline
population genetics
single nucleotide polymorphism
zebrafish

ASJC Scopus subject areas

Nephrology

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10.1038/ki.2014.361

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Gorski, M., Tin, A., Garnaas, M., McMahon, G. M., Chu, A. Y., Tayo, B. O., Pattaro, C., Teumer, A., Chasman, D. I., Chalmers, J., Hamet, P., Tremblay, J., Woodward, M., Aspelund, T., Eiriksdottir, G., Gudnason, V., Harris, T. B., Launer, L. J., Smith, A. V., ... Böger, C. A. (2015). Genome-wide association study of kidney function decline in individuals of European descent. Kidney international, 87(5), 1017-1029. https://doi.org/10.1038/ki.2014.361

Gorski, M, Tin, A, Garnaas, M, McMahon, GM, Chu, AY, Tayo, BO, Pattaro, C, Teumer, A, Chasman, DI, Chalmers, J, Hamet, P, Tremblay, J, Woodward, M, Aspelund, T, Eiriksdottir, G, Gudnason, V, Harris, TB, Launer, LJ, Smith, AV, Mitchell, BD, O'Connell, JR, Shuldiner, AR, Coresh, J, Li, M, Freudenberger, P, Hofer, E, Schmidt, H, Schmidt, R, Holliday, EG, Mitchell, P, Wang, JJ, De Boer, IH, Li, G, Siscovick, DS, Kutalik, Z, Corre, T, Vollenweider, P, Waeber, G, Gupta, J, Kanetsky, PA, Hwang, SJ, Olden, M, Yang, Q, De Andrade, M, Atkinson, EJ, Kardia, SLR, Turner, ST, Stafford, JM, Ding, J, Liu, Y, Barlassina, C, Cusi, D, Salvi, E, Staessen, JA, Ridker, PM, Grallert, H, Meisinger, C, Müller-Nurasyid, M, Krämer, BK, Kramer, H, Rosas, SE, Nolte, IM, Penninx, BW, Snieder, H, Fabiola Del Greco, M, Franke, A, Nöthlings, U, Lieb, W, Bakker, SJL, Gansevoort, RT, Van Der Harst, P, Dehghan, A, Franco, OH, Hofman, A, Rivadeneira, F, Sedaghat, S, Uitterlinden, AG, Coassin, S, Haun, M, Kollerits, B, Kronenberg, F, Paulweber, B, Aumann, N, Endlich, K, Pietzner, M, Völker, U, Rettig, R, Chouraki, V, Helmer, C, Lambert, JC, Metzger, M, Stengel, B, Lehtimäki, T, Lyytikäinen, LP, Raitakari, O, Johnson, A, Parsa, A, Bochud, M, Heid, IM, Goessling, W, Köttgen, A, Kao, WHL, Fox, CS & Böger, CA 2015, 'Genome-wide association study of kidney function decline in individuals of European descent', Kidney international, vol. 87, no. 5, pp. 1017-1029. https://doi.org/10.1038/ki.2014.361

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title = "Genome-wide association study of kidney function decline in individuals of European descent",

abstract = "Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m 2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.",

keywords = "chronic kidney disease, genome-wide association study, kidney development, kidney function decline, population genetics, single nucleotide polymorphism, zebrafish",

author = "Mathias Gorski and Adrienne Tin and Maija Garnaas and McMahon, {Gearoid M.} and Chu, {Audrey Y.} and Tayo, {Bamidele O.} and Cristian Pattaro and Alexander Teumer and Chasman, {Daniel I.} and John Chalmers and Pavel Hamet and Johanne Tremblay and Marc Woodward and Thor Aspelund and Gudny Eiriksdottir and Vilmundur Gudnason and Harris, {Tamara B.} and Launer, {Lenore J.} and Smith, {Albert V.} and Mitchell, {Braxton D.} and O'Connell, {Jeffrey R.} and Shuldiner, {Alan R.} and Josef Coresh and Man Li and Paul Freudenberger and Edith Hofer and Helena Schmidt and Reinhold Schmidt and Holliday, {Elizabeth G.} and Paul Mitchell and Wang, {Jie Jin} and {De Boer}, {Ian H.} and Guo Li and Siscovick, {David S.} and Zoltan Kutalik and Tanguy Corre and Peter Vollenweider and G{\'e}rard Waeber and Jayanta Gupta and Kanetsky, {Peter A.} and Hwang, {Shih Jen} and Matthias Olden and Qiong Yang and {De Andrade}, Mariza and Atkinson, {Elizabeth J.} and Kardia, {Sharon L.R.} and Turner, {Stephen T.} and Stafford, {Jeanette M.} and Jingzhong Ding and Yongmei Liu and Cristina Barlassina and Daniele Cusi and Erika Salvi and Staessen, {Jan A.} and Ridker, {Paul M.} and Harald Grallert and Christa Meisinger and Martina M{\"u}ller-Nurasyid and Kr{\"a}mer, {Bernhard K.} and Holly Kramer and Rosas, {Sylvia E.} and Nolte, {Ilja M.} and Penninx, {Brenda W.} and Harold Snieder and {Fabiola Del Greco}, M. and Andre Franke and Ute N{\"o}thlings and Wolfgang Lieb and Bakker, {Stephan J.L.} and Gansevoort, {Ron T.} and {Van Der Harst}, Pim and Abbas Dehghan and Franco, {Oscar H.} and Albert Hofman and Fernando Rivadeneira and Sanaz Sedaghat and Uitterlinden, {Andr{\'e} G.} and Stefan Coassin and Margot Haun and Barbara Kollerits and Florian Kronenberg and Bernhard Paulweber and Nicole Aumann and Karlhans Endlich and Mike Pietzner and Uwe V{\"o}lker and Rainer Rettig and Vincent Chouraki and Catherine Helmer and Lambert, {Jean Charles} and Marie Metzger and Benedicte Stengel and Terho Lehtim{\"a}ki and Lyytik{\"a}inen, {Leo Pekka} and Olli Raitakari and Andrew Johnson and Afshin Parsa and Murielle Bochud and Heid, {Iris M.} and Wolfram Goessling and Anna K{\"o}ttgen and Kao, {W. H.Linda} and Fox, {Caroline S.} and B{\"o}ger, {Carsten A.}",

note = "Publisher Copyright: {\textcopyright} 2014 International Society of Nephrology.",

year = "2015",

month = may,

day = "11",

doi = "10.1038/ki.2014.361",

language = "English (US)",

volume = "87",

pages = "1017--1029",

journal = "Kidney international",

issn = "0085-2538",

publisher = "Nature Publishing Group",

number = "5",

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TY - JOUR

T1 - Genome-wide association study of kidney function decline in individuals of European descent

AU - Gorski, Mathias

AU - Tin, Adrienne

AU - Garnaas, Maija

AU - McMahon, Gearoid M.

AU - Chu, Audrey Y.

AU - Tayo, Bamidele O.

AU - Pattaro, Cristian

AU - Teumer, Alexander

AU - Chasman, Daniel I.

AU - Chalmers, John

AU - Hamet, Pavel

AU - Tremblay, Johanne

AU - Woodward, Marc

AU - Aspelund, Thor

AU - Eiriksdottir, Gudny

AU - Gudnason, Vilmundur

AU - Harris, Tamara B.

AU - Launer, Lenore J.

AU - Smith, Albert V.

AU - Mitchell, Braxton D.

AU - O'Connell, Jeffrey R.

AU - Shuldiner, Alan R.

AU - Coresh, Josef

AU - Li, Man

AU - Freudenberger, Paul

AU - Hofer, Edith

AU - Schmidt, Helena

AU - Schmidt, Reinhold

AU - Holliday, Elizabeth G.

AU - Mitchell, Paul

AU - Wang, Jie Jin

AU - De Boer, Ian H.

AU - Li, Guo

AU - Siscovick, David S.

AU - Kutalik, Zoltan

AU - Corre, Tanguy

AU - Vollenweider, Peter

AU - Waeber, Gérard

AU - Gupta, Jayanta

AU - Kanetsky, Peter A.

AU - Hwang, Shih Jen

AU - Olden, Matthias

AU - Yang, Qiong

AU - De Andrade, Mariza

AU - Atkinson, Elizabeth J.

AU - Kardia, Sharon L.R.

AU - Turner, Stephen T.

AU - Stafford, Jeanette M.

AU - Ding, Jingzhong

AU - Liu, Yongmei

AU - Barlassina, Cristina

AU - Cusi, Daniele

AU - Salvi, Erika

AU - Staessen, Jan A.

AU - Ridker, Paul M.

AU - Grallert, Harald

AU - Meisinger, Christa

AU - Müller-Nurasyid, Martina

AU - Krämer, Bernhard K.

AU - Kramer, Holly

AU - Rosas, Sylvia E.

AU - Nolte, Ilja M.

AU - Penninx, Brenda W.

AU - Snieder, Harold

AU - Fabiola Del Greco, M.

AU - Franke, Andre

AU - Nöthlings, Ute

AU - Lieb, Wolfgang

AU - Bakker, Stephan J.L.

AU - Gansevoort, Ron T.

AU - Van Der Harst, Pim

AU - Dehghan, Abbas

AU - Franco, Oscar H.

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - Sedaghat, Sanaz

AU - Uitterlinden, André G.

AU - Coassin, Stefan

AU - Haun, Margot

AU - Kollerits, Barbara

AU - Kronenberg, Florian

AU - Paulweber, Bernhard

AU - Aumann, Nicole

AU - Endlich, Karlhans

AU - Pietzner, Mike

AU - Völker, Uwe

AU - Rettig, Rainer

AU - Chouraki, Vincent

AU - Helmer, Catherine

AU - Lambert, Jean Charles

AU - Metzger, Marie

AU - Stengel, Benedicte

AU - Lehtimäki, Terho

AU - Lyytikäinen, Leo Pekka

AU - Raitakari, Olli

AU - Johnson, Andrew

AU - Parsa, Afshin

AU - Bochud, Murielle

AU - Heid, Iris M.

AU - Goessling, Wolfram

AU - Köttgen, Anna

AU - Kao, W. H.Linda

AU - Fox, Caroline S.

AU - Böger, Carsten A.

PY - 2015/5/11

Y1 - 2015/5/11

N2 - Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m 2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

AB - Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m 2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

KW - chronic kidney disease

KW - genome-wide association study

KW - kidney development

KW - kidney function decline

KW - population genetics

KW - single nucleotide polymorphism

KW - zebrafish

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U2 - 10.1038/ki.2014.361

DO - 10.1038/ki.2014.361

M3 - Article

C2 - 25493955

AN - SCOPUS:84929128445

SN - 0085-2538

VL - 87

SP - 1017

EP - 1029

JO - Kidney international

JF - Kidney international

IS - 5

ER -

Genome-wide association study of kidney function decline in individuals of European descent

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