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*

*Corresponding author for this work

Research output: Contribution to journalArticle

67 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 languageEnglish (US)
Pages (from-to)1017-1029
Number of pages13
JournalKidney international
Volume87
Issue number5
DOIs
StatePublished - 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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    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