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

M. Gorski; A. Tin; M. Garnaas; G.M. McMahon; A.Y. Chu; B.O. Tayo; C. Pattaro; A. Teumer; D.I. Chasman; J. Chalmers; P. Hamet; J. Tremblay; M. Woodward; T. Aspelund; G. Eiriksdottir; V. Gudnason; T.B. Harris; L.J. Launer; A.V. Smith; B.D. Mitchell; J.R. O'Connell; A.R. Shuldiner; J. Coresh; M. Li; P. Freudenberger; E. Hofer; H. Schmidt; R. Schmidt; E.G. Holliday; P. Mitchell; J.J. Wang; I.H. de Boer; G. Li; D.S. Siscovick; Z. Kutalik; T. Corre; P. Vollenweider; G. Waeber; J. Gupta; P.A. Kanetsky; S.J. Hwang; M. Olden; Q. Yang; M. de Andrade; E.J. Atkinson; S.L.R. Kardia; S.T. Turner; J.M. Stafford; J.Z. Ding; Y.M. Liu; C. Barlassina; D. Cusi; E. Salvi; J.A. Staessen; P.M. Ridker; H. Grallert; C. Meisinger; M. Muller-Nurasyid; B.K. Kramer; H. Kramer; S.E. Rosas; I.M. Nolte; B.W.J.H. Penninx; H. Snieder; M.F. Del Greco; A. Franke; U. Nothlings; W. Lieb; S.J.L. Bakker; R.T. Gansevoort; P. van der Harst; A. Dehghan; O.H. Franco; A. Hofman; F. Rivadeneira; S. Sedaghat; A. G. Uitterlinden; S. Coassin; M. Haun; B. Kollerits; F. Kronenberg; B. Paulweber; N. Aumann; K. Endlich; M. Pietzner; U. Volker; R. Rettig; V. Chouraki; C. Helmer; J.C. Lambert; M. Metzger; B. Stengel; T. Lehtimaki; L.P. Lyytikainen; O. Raitakari; A. Johnson; A. Parsa; M. Bochud; I.M. Heid

doi:10.1038/ki.2014.361

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

M. Gorski, A. Tin, M. Garnaas, G.M. McMahon, A.Y. Chu, B.O. Tayo, C. Pattaro, A. Teumer, D.I. Chasman, J. Chalmers, P. Hamet, J. Tremblay, M. Woodward, T. Aspelund, G. Eiriksdottir, V. Gudnason, T.B. Harris, L.J. Launer, A.V. Smith, B.D. MitchellJ.R. O'Connell, A.R. Shuldiner, J. Coresh, M. Li, P. Freudenberger, E. Hofer, H. Schmidt, R. Schmidt, E.G. Holliday, P. Mitchell, J.J. Wang, I.H. de Boer, G. Li, D.S. Siscovick, Z. Kutalik, T. Corre, P. Vollenweider, G. Waeber, J. Gupta, P.A. Kanetsky, S.J. Hwang, M. Olden, Q. Yang, M. de Andrade, E.J. Atkinson, S.L.R. Kardia, S.T. Turner, J.M. Stafford, J.Z. Ding, Y.M. Liu, C. Barlassina, D. Cusi, E. Salvi, J.A. Staessen, P.M. Ridker, H. Grallert, C. Meisinger, M. Muller-Nurasyid, B.K. Kramer, H. Kramer, S.E. Rosas, I.M. Nolte, B.W.J.H. Penninx, H. Snieder, M.F. Del Greco, A. Franke, U. Nothlings, W. Lieb, S.J.L. Bakker, R.T. Gansevoort, P. van der Harst, A. Dehghan, O.H. Franco, A. Hofman, F. Rivadeneira, S. Sedaghat, A. G. Uitterlinden, S. Coassin, M. Haun, B. Kollerits, F. Kronenberg, B. Paulweber, N. Aumann, K. Endlich, M. Pietzner, U. Volker, R. Rettig, V. Chouraki, C. Helmer, J.C. Lambert, M. Metzger, B. Stengel, T. Lehtimaki, L.P. Lyytikainen, O. Raitakari, A. Johnson, A. Parsa, M. Bochud, I.M. Heid

Research output: Contribution to Journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	1017-1029
Journal	Kidney International
Volume	87
Issue number	5
DOIs	https://doi.org/10.1038/ki.2014.361
Publication status	Published - 2015

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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., ... Heid, I. M. (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

@article{a65f0a28d7b24793abc0750f74ea1f1e,

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 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.",

author = "M. Gorski and A. Tin and M. Garnaas and G.M. McMahon and A.Y. Chu and B.O. Tayo and C. Pattaro and A. Teumer and D.I. Chasman and J. Chalmers and P. Hamet and J. Tremblay and M. Woodward and T. Aspelund and G. Eiriksdottir and V. Gudnason and T.B. Harris and L.J. Launer and A.V. Smith and B.D. Mitchell and J.R. O'Connell and A.R. Shuldiner and J. Coresh and M. Li and P. Freudenberger and E. Hofer and H. Schmidt and R. Schmidt and E.G. Holliday and P. Mitchell and J.J. Wang and {de Boer}, I.H. and G. Li and D.S. Siscovick and Z. Kutalik and T. Corre and P. Vollenweider and G. Waeber and J. Gupta and P.A. Kanetsky and S.J. Hwang and M. Olden and Q. Yang and {de Andrade}, M. and E.J. Atkinson and S.L.R. Kardia and S.T. Turner and J.M. Stafford and J.Z. Ding and Y.M. Liu and C. Barlassina and D. Cusi and E. Salvi and J.A. Staessen and P.M. Ridker and H. Grallert and C. Meisinger and M. Muller-Nurasyid and B.K. Kramer and H. Kramer and S.E. Rosas and I.M. Nolte and B.W.J.H. Penninx and H. Snieder and {Del Greco}, M.F. and A. Franke and U. Nothlings and W. Lieb and S.J.L. Bakker and R.T. Gansevoort and {van der Harst}, P. and A. Dehghan and O.H. Franco and A. Hofman and F. Rivadeneira and S. Sedaghat and Uitterlinden, {A. G.} and S. Coassin and M. Haun and B. Kollerits and F. Kronenberg and B. Paulweber and N. Aumann and K. Endlich and M. Pietzner and U. Volker and R. Rettig and V. Chouraki and C. Helmer and J.C. Lambert and M. Metzger and B. Stengel and T. Lehtimaki and L.P. Lyytikainen and O. Raitakari and A. Johnson and A. Parsa and M. Bochud and I.M. Heid",

year = "2015",

doi = "10.1038/ki.2014.361",

language = "English",

volume = "87",

pages = "1017--1029",

journal = "Kidney International",

issn = "0085-2538",

publisher = "Nature Publishing Group",

number = "5",

}

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, BWJH, 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 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

TY - JOUR

T1 - Genome-wide association study of kidney function decline in individuals of European descent

AU - Gorski, M.

AU - Tin, A.

AU - Garnaas, M.

AU - McMahon, G.M.

AU - Chu, A.Y.

AU - Tayo, B.O.

AU - Pattaro, C.

AU - Teumer, A.

AU - Chasman, D.I.

AU - Chalmers, J.

AU - Hamet, P.

AU - Tremblay, J.

AU - Woodward, M.

AU - Aspelund, T.

AU - Eiriksdottir, G.

AU - Gudnason, V.

AU - Harris, T.B.

AU - Launer, L.J.

AU - Smith, A.V.

AU - Mitchell, B.D.

AU - O'Connell, J.R.

AU - Shuldiner, A.R.

AU - Coresh, J.

AU - Li, M.

AU - Freudenberger, P.

AU - Hofer, E.

AU - Schmidt, H.

AU - Schmidt, R.

AU - Holliday, E.G.

AU - Mitchell, P.

AU - Wang, J.J.

AU - de Boer, I.H.

AU - Li, G.

AU - Siscovick, D.S.

AU - Kutalik, Z.

AU - Corre, T.

AU - Vollenweider, P.

AU - Waeber, G.

AU - Gupta, J.

AU - Kanetsky, P.A.

AU - Hwang, S.J.

AU - Olden, M.

AU - Yang, Q.

AU - de Andrade, M.

AU - Atkinson, E.J.

AU - Kardia, S.L.R.

AU - Turner, S.T.

AU - Stafford, J.M.

AU - Ding, J.Z.

AU - Liu, Y.M.

AU - Barlassina, C.

AU - Cusi, D.

AU - Salvi, E.

AU - Staessen, J.A.

AU - Ridker, P.M.

AU - Grallert, H.

AU - Meisinger, C.

AU - Muller-Nurasyid, M.

AU - Kramer, B.K.

AU - Kramer, H.

AU - Rosas, S.E.

AU - Nolte, I.M.

AU - Penninx, B.W.J.H.

AU - Snieder, H.

AU - Del Greco, M.F.

AU - Franke, A.

AU - Nothlings, U.

AU - Lieb, W.

AU - Bakker, S.J.L.

AU - Gansevoort, R.T.

AU - van der Harst, P.

AU - Dehghan, A.

AU - Franco, O.H.

AU - Hofman, A.

AU - Rivadeneira, F.

AU - Sedaghat, S.

AU - Uitterlinden, A. G.

AU - Coassin, S.

AU - Haun, M.

AU - Kollerits, B.

AU - Kronenberg, F.

AU - Paulweber, B.

AU - Aumann, N.

AU - Endlich, K.

AU - Pietzner, M.

AU - Volker, U.

AU - Rettig, R.

AU - Chouraki, V.

AU - Helmer, C.

AU - Lambert, J.C.

AU - Metzger, M.

AU - Stengel, B.

AU - Lehtimaki, T.

AU - Lyytikainen, L.P.

AU - Raitakari, O.

AU - Johnson, A.

AU - Parsa, A.

AU - Bochud, M.

AU - Heid, I.M.

PY - 2015

Y1 - 2015

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.

U2 - 10.1038/ki.2014.361

DO - 10.1038/ki.2014.361

M3 - Article

SN - 0085-2538

VL - 87

SP - 1017

EP - 1029

JO - Kidney International

JF - Kidney International

IS - 5

ER -

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

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