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 & 84 others 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)1017-1029
Number of pages13
JournalKidney International
Volume87
Issue number5
DOIs
StatePublished - May 11 2015

Fingerprint

Genome-Wide Association Study
Meta-Analysis
Kidney
Gentamicins
Morpholinos
Zebrafish
Single Nucleotide Polymorphism
Edema
Embryonic Structures
Genome

Keywords

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

ASJC Scopus subject areas

  • Nephrology

Cite this

Gorski, M., Tin, A., Garnaas, M., McMahon, G. M., Chu, A. Y., Tayo, B. O., ... 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

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

In: Kidney International, Vol. 87, No. 5, 11.05.2015, p. 1017-1029.

Research output: Contribution to journalArticle

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
Gorski, Mathias ; Tin, Adrienne ; Garnaas, Maija ; McMahon, Gearoid M. ; Chu, Audrey Y. ; Tayo, Bamidele O. ; Pattaro, Cristian ; Teumer, Alexander ; Chasman, Daniel I. ; Chalmers, John ; Hamet, Pavel ; Tremblay, Johanne ; Woodward, Marc ; Aspelund, Thor ; Eiriksdottir, Gudny ; Gudnason, Vilmundur ; Harris, Tamara B. ; Launer, Lenore J. ; Smith, Albert V. ; Mitchell, Braxton D. ; O'Connell, Jeffrey R. ; Shuldiner, Alan R. ; Coresh, Josef ; Li, Man ; Freudenberger, Paul ; Hofer, Edith ; Schmidt, Helena ; Schmidt, Reinhold ; Holliday, Elizabeth G. ; Mitchell, Paul ; Wang, Jie Jin ; De Boer, Ian H. ; Li, Guo ; Siscovick, David S. ; Kutalik, Zoltan ; Corre, Tanguy ; Vollenweider, Peter ; Waeber, Gérard ; Gupta, Jayanta ; Kanetsky, Peter A. ; Hwang, Shih Jen ; Olden, Matthias ; Yang, Qiong ; De Andrade, Mariza ; Atkinson, Elizabeth J. ; Kardia, Sharon L R ; Turner, Stephen T. ; Stafford, Jeanette M. ; Ding, Jingzhong ; Liu, Yongmei ; Barlassina, Cristina ; Cusi, Daniele ; Salvi, Erika ; Staessen, Jan A. ; Ridker, Paul M. ; Grallert, Harald ; Meisinger, Christa ; Müller-Nurasyid, Martina ; Krämer, Bernhard K. ; Kramer, Holly ; Rosas, Sylvia E. ; Nolte, Ilja M. ; Penninx, Brenda W. ; Snieder, Harold ; Fabiola Del Greco, M. ; Franke, Andre ; Nöthlings, Ute ; Lieb, Wolfgang ; Bakker, Stephan J L ; Gansevoort, Ron T. ; Van Der Harst, Pim ; Dehghan, Abbas ; Franco, Oscar H. ; Hofman, Albert ; Rivadeneira, Fernando ; Sedaghat, Sanaz ; Uitterlinden, André G. ; Coassin, Stefan ; Haun, Margot ; Kollerits, Barbara ; Kronenberg, Florian ; Paulweber, Bernhard ; Aumann, Nicole ; Endlich, Karlhans ; Pietzner, Mike ; Völker, Uwe ; Rettig, Rainer ; Chouraki, Vincent ; Helmer, Catherine ; Lambert, Jean Charles ; Metzger, Marie ; Stengel, Benedicte ; Lehtimäki, Terho ; Lyytikäinen, Leo Pekka ; Raitakari, Olli ; Johnson, Andrew ; Parsa, Afshin ; Bochud, Murielle ; Heid, Iris M. ; Goessling, Wolfram ; Köttgen, Anna ; Kao, W. H Linda ; Fox, Caroline S. ; Böger, Carsten A. / Genome-wide association study of kidney function decline in individuals of European descent. In: Kidney International. 2015 ; Vol. 87, No. 5. pp. 1017-1029.
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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

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JF - Kidney International

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