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


Authors: 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.; Mitchell, B. D.; O'Connell, J. R.; Shuldiner, A. R.; Coresh, J; Li, M; Freudenberger, P.; Hofer, E; Schmidt, H; Schmidt, R; Holliday, E. G.; Mitchell, P; Wang, J. J.; de Boer, I. H.; Li, G; Siscovick, D. S.; Kutalik, Z; Corre, T; Vollenweider, P; Waeber, G; Gupta, J.; Kanetsky, P. A.; Hwang, S. J.; Olden, M; Yang, Q; de Andrade, M; Atkinson, E. J.; Kardia, S. L.; Turner, S. T.; Stafford, J. M.; Ding, J; Liu, Y; Barlassina, C.; Cusi, D; Salvi, E; Staessen, J. A.; Ridker, P. M.; Grallert, H; Meisinger, C; Muller-Nurasyid, M.; Kramer, B. K.; Kramer, H; Rosas, S. E.; Nolte, I. M.; Penninx, B. W.; Snieder, H; Fabiola Del Greco, M.; Franke, A; Nothlings, U.; Lieb, W; Bakker, S. J.; Gansevoort, R. T.; van der Harst, P; Dehghan, A; Franco, O. H.; Hofman, A; Rivadeneira, F; Sedaghat, S; Uitterlinden, A. G.; 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, J. C.; Metzger, M; Stengel, B; Lehtimaki, T.; Lyytikainen, L. P.; Raitakari, O; Johnson, A; Parsa, A; Bochud, M; Heid, I. M.; Goessling, W.; Kottgen, A.; Kao, W. H.; Fox, C. S.; Boger, C. A.
Article 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 m2 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: Public Health Services
Journal Title: Kidney international
Volume: 87
Issue: 5
ISSN: 1523-1755; 0085-2538
Publisher: Unknown  
Date Published: 2015
Start Page: 1017
End Page: 1029
Language: ENG
DOI/URL:
Notes: LR: 20150924; GR: 1 R01 DK075787-01A1/DK/NIDDK NIH HHS/United States; GR: 1R01AG032098-01A1/AG/NIA NIH HHS/United States; GR: DK063491/DK/NIDDK NIH HHS/United States; GR: HHSN268200625226C/PHS HHS/United States; GR: HHSN268200782096C/PHS HHS/United States; GR: HHSN268201100005C/PHS HHS/United States; GR: HHSN268201100006C/PHS HHS/United States; GR: HHSN268201100007C/PHS HHS/United States; GR: HHSN268201100008C/PHS HHS/United States; GR: HHSN268201100009C/PHS HHS/United States; GR: HHSN268201100010C/PHS HHS/United States; GR: HHSN268201100011C/PHS HHS/United States; GR: HHSN268201100012C/PHS HHS/United States; GR: K12RR023250/RR/NCRR NIH HHS/United States; GR: M01 RR 16500/RR/NCRR NIH HHS/United States; GR: M01RR00425/RR/NCRR NIH HHS/United States; GR: MH081802/MH/NIMH NIH HHS/United States; GR: N01 HC-15103/HC/NHLBI NIH HHS/United States; GR: N01 HC-55222/HC/NHLBI NIH HHS/United States; GR: N01-AG-1-2100/AG/NIA NIH HHS/United States; GR: N01-HC-25195/HC/NHLBI NIH HHS/United States; GR: N01-HC-35129/HC/NHLBI NIH HHS/United States; GR: N01-HC-45133/HC/NHLBI NIH HHS/United States; GR: N01-HC-75150/HC/NHLBI NIH HHS/United States; GR: N01-HC-85079-01-HC-85086/HC/NHLBI NIH HHS/United States; GR: N01-HC-95159/HC/NHLBI NIH HHS/United States; GR: N01-HC-95160/HC/NHLBI NIH HHS/United States; GR: N01-HC-95161/HC/NHLBI NIH HHS/United States; GR: N01-HC-95162/HC/NHLBI NIH HHS/United States; GR: N01-HC-95163/HC/NHLBI NIH HHS/United States; GR: N01-HC-95164/HC/NHLBI NIH HHS/United States; GR: N01-HC-95165/HC/NHLBI NIH HHS/United States; GR: N01-HC-95166/HC/NHLBI NIH HHS/United States; GR: N01-HC-95167/HC/NHLBI NIH HHS/United States; GR: N01-HC-95168/HC/NHLBI NIH HHS/United States; GR: N01-HC-95169/HC/NHLBI NIH HHS/United States; GR: N01AG62101/AG/NIA NIH HHS/United States; GR: N01AG62103/AG/NIA NIH HHS/United States; GR: N01AG62106/AG/NIA NIH HHS/United States; GR: N02-HL-6-4278/HL/NHLBI NIH HHS/United States; GR: P30 DK017047/DK/NIDDK NIH HHS/United States; GR: P30 DK072488/DK/NIDDK NIH HHS/United States; GR: R01 AG018728/AG/NIA NIH HHS/United States; GR: R01 AG18728/AG/NIA NIH HHS/United States; GR: R01 DK090311/DK/NIDDK NIH HHS/United States; GR: R01 HL-87660/HL/NHLBI NIH HHS/United States; GR: R01 HL087652/HL/NHLBI NIH HHS/United States; GR: R01 HL088119/HL/NHLBI NIH HHS/United States; GR: R01 HL088119/HL/NHLBI NIH HHS/United States; GR: R01 MH059160/MH/NIMH NIH HHS/United States; GR: R01HL086694/HL/NHLBI NIH HHS/United States; GR: R01HL087641/HL/NHLBI NIH HHS/United States; GR: R01HL59367/HL/NHLBI NIH HHS/United States; GR: R24 OD017870/OD/NIH HHS/United States; GR: U01 GM074518-04/GM/NIGMS NIH HHS/United States; GR: U01 HL072515-06/HL/NHLBI NIH HHS/United States; GR: U01 HL080295/HL/NHLBI NIH HHS/United States; GR: U01 HL084756/HL/NHLBI NIH HHS/United States; GR: U01HG004402/HG/NHGRI NIH HHS/United States; GR: UL1 TR000135/TR/NCATS NIH HHS/United States; GR: UL1-RR-024156/RR/NCRR NIH HHS/United States; GR: UL1RR025005/RR/NCRR NIH HHS/United States; GR: Intramural NIH HHS/United States; JID: 0323470; NIHMS638325; OID: NLM: NIHMS638325 [Available on 11/01/15]; OID: NLM: PMC4425568 [Available on 11/01/15]; PMCR: 2015/11/01 00:00; 2014/01/31 [received]; 2014/09/04 [revised]; 2014/09/11 [accepted]; 2014/12/10 [aheadofprint]; ppublish