Genome-wide association study of kidney function decline in individuals of European descent
: 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 JZ, Liu YM, Barlassina C, Cusi D, Salvi E, Staessen JA, Ridker PM, Grallert H, Meisinger C, Muller-Nurasyid M, Kramer BK, Kramer H, Rosas SE, Nolte IM, Penninx BW, Snieder H, Del Greco MF, Franke A, Nothlings 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, Volker U, Rettig R, Chouraki V, Helmer C, Lambert JC, Metzger M, Stengel B, Lehtimaki T, Lyytikainen LP, Raitakari O, Johnson A, Parsa A, Bochud M, Heid IM, Goessling W, Kottgen A, Kao WHL, Fox CS, Boger CA
Publisher: NATURE PUBLISHING GROUP
: 2015
Kidney International
: KIDNEY INTERNATIONAL
: KIDNEY INT
: 87
: 5
: 1017
: 1029
: 13
: 0085-2538
: 1523-1755
DOI: https://doi.org/10.1038/ki.2014.361
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 1.73m(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.
