Journal Article

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

de Andrade, Mariza, Fox, Caroline S., Siscovick, David S., Hwang, Shih-Jen, Cusi, Daniele, Paulweber, Bernhard, Bakker, Stephan J.L., de Boer, Ian H., Gudnason, Vilmundur, Holliday, Elizabeth G., Mitchell, Braxton D., Yang, Qiong, Wang, Jie Jin, Nolte, Ilja M., Liu, Yongmei, Heid, Iris M., Eiriksdottir, Gudny, Franke, Andre, Chalmers, John, Kanetsky, Peter A., Hofer, Edith, Rettig, Rainer, Vollenweider, Peter, Parsa, Afshin, Sedaghat, Sanaz, van der Harst, Pim, Schmidt, Helena, McMahon, Gearoid M., Shuldiner, Alan R., Waeber, Gérard, Johnson, Andrew, Bochud, Murielle, Kutalik, Zoltan, Dehghan, Abbas, Stengel, Benedicte, Gupta, Jayanta, Nöthlings, Ute, Köttgen, Anna, Freudenberger, Paul, Turner, Stephen T., Kronenberg, Florian, Atkinson, Elizabeth J., Goessling, Wolfram, Müller-Nurasyid, Martina, Tin, Adrienne, Schmidt, Reinhold, Ding, Jingzhong, Uitterlinden, André G., Meisinger, Christa, Franco, Oscar H., Kardia, Sharon L.R., Penninx, Brenda W., Haun, Margot, Gansevoort, Ron T., Smith, Albert V., Lambert, Jean-Charles, Böger, Carsten A., Krämer, Bernhard K., Fabiola Del Greco, M., Linda Kao, W.H., Corr

2015

Overview

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 3ml/min per 1.73m2 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 72h 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.

• Publisher: Elsevier Inc,Elsevier Limited
• Subject: Animals / Cadherin Related Proteins / Cadherins - genetics / chronic kidney disease / Genome, Human / Genome-Wide Association Study / Glomerular Filtration Rate - genetics / Humans / kidney development / kidney function decline / N-Acetylgalactosaminyltransferases - genetics / population genetics / Renal Insufficiency - genetics / single nucleotide polymorphism / Uromodulin - genetics / White People - genetics / zebrafish