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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

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posted on 2016-11-09, 16:08 authored by C. Pattaro, A. Teumer, M. Gorski, A. Y. Chu, M. Li, V. Mijatovic, M. Garnaas, A. Tin, R. Sorice, Y. Li, D. Taliun, M. Olden, M. Foster, Q. Yang, M. H. Chen, T. H. Pers, A. D. Johnson, Y. A. Ko, C. Fuchsberger, B. Tayo, M. Nalls, M. F. Feitosa, A. Isaacs, A. Dehghan, P. D'Adamo, A. Adeyemo, A. K. Dieffenbach, A. B. Zonderman, I. M. Nolte, P. J. Van Der Most, A. F. Wright, A. R. Shuldiner, A. C. Morrison, A. Hofman, A. V. Smith, A. W. Dreisbach, A. Franke, A. G. Uitterlinden, A. Metspalu, A. Tonjes, A. Lupo, A. Robino, Å. Johansson, A. Demirkan, B. Kollerits, B. I. Freedman, B. Ponte, B. A. Oostra, B. Paulweber, B. K. Krämer, B. D. Mitchell, B. M. Buckley, C. A. Peralta, C. Hayward, C. Helmer, C. N. Rotimi, C. M. Shaffer, C. Müller, C. Sala, C. M. Van Duijn, A. Saint-Pierre, D. Ackermann, D. Shriner, D. Ruggiero, D. Toniolo, Y. Lu, D. Cusi, D. Czamara, D. Ellinghaus, D. S. Siscovick, D. Ruderfer, C. Gieger, H. Grallert, E. Rochtchina, E. J. Atkinson, E. G. Holliday, E. Boerwinkle, E. Salvi, E. P. Bottinger, F. Murgia, F. Rivadeneira, F. Ernst, F. Kronenberg, F. B. Hu, G. J. Navis, G. C. Curhan, G. B. Ehret, G. Homuth, S. Coassin, G-A. Thun, G. Pistis, G. Gambaro, G. Malerba, G. W. Montgomery, G. Eiriksdottir, G. Jacobs, G. Li, H-E. Wichmann, H. Campbell, H. Schmidt, H. Wallaschofski, H. Völzke, H. Brenner, H. K. Kroemer, H. Kramer, H. Lin, I. M. Leach, I. Ford, I. Guessous, I. Rudan, I. Prokopenko, I. Borecki, I. M. Heid, I. Kolcic, I. Persico, J. W. Jukema, J. F. Wilson, J. F. Felix, J. Divers, J-C. Lambert, J. M. Stafford, J-M. Gaspoz, J. A. Smith, J. D. Faul, J. J. Wang, J. Ding, J. N. Hirschhorn, J. Attia, J. B. Whitfield, J. Chalmers, J. Viikari, J. Coresh, J. C. Denny, J. Karjalainen, J. K. Fernandes, K. Endlich, K. Butterbach, K. L. Keene, K. Lohman, L. Portas, L. J. Launer, L-P. Lyytikäinen, L. Yengo, L. Franke, L. Ferrucci, L. M. Rose, L. Kedenko, M. Rao, M. Struchalin, M. E. Kleber, M. Cavalieri, M. Haun, M. C. Cornelis, M. Ciullo, M. Pirastu, M. de Andrade, M. A. McEvoy, M. Woodward, M. Adam, M. Cocca, M. Nauck, M. Imboden, M. Waldenberger, M. Pruijm, M. Metzger, M. Stumvoll, M. K. Evans, M. M. Sale, M. Kähönen, M. Boban, M. Bochud, M. Rheinberger, N. Verweij, N. Bouatia-Naji, N. G. Martin, N. Hastie, N. Probst-Hensch, N. Soranzo, O. Devuyst, O. Raitakari, O. Gottesman, O. H. Franco, O. Polasek, P. Gasparini, P. B. Munroe, P. M. Ridker, P. Mitchell, P. Muntner, C. Meisinger, J. H. Smit, ICBP Consortium, AGEN Consortium, CARDIOGRAM, CHARGe-Heart Failure Group, ECHOGen Consortium, P. Kovacs, P. S. Wild, P. Froguel, R. Rettig, R. Mägi, R. Biffar, R. Schmidt, R. P. S. Middelberg, R. J. Carroll, B. W. Penninx, R. J. Scott, R. Katz, S. Sedaghat, S. H. Wild, S. L. R. Kardia, S. Ulivi, S-J. Hwang, S. Enroth, S. Kloiber, S. Trompet, B. Stengel, S. J. Hancock, S. T. Turner, S. E. Rosas, S. Stracke, T. B. Harris, T. Zeller, T. Zemunik, T. Lehtimäki, T. Illig, T. Aspelund, T. Nikopensius, T. Esko, T. Tanaka, U. Gyllensten, U. Völker, V. Emilsson, V. Vitart, V. Aalto, V. Gudnason, V. Chouraki, W-M. Chen, W. Igl, W. März, W. Koenig, W. Lieb, Y. Liu, R. J. F. Loos, H. Snieder, P. P. Pramstaller, A. Parsa, J. R. O’Connell, K. Susztak, P. Hamet, J. Tremblay, I. H. de Boer, C. A. Böger, W. Goessling, D. I. Chasman, A. Köttgen, W. H. L. Kao, C. S. Fox
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Funding

Study-specific acknowledgements and funding sources for participating studies are reported in Supplementary Note. Zebrafish work was supported by NIH R01DK090311 and R24OD017870 to W.G.

History

Citation

Nature Communications, 2016, 7:10023

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

Version

  • VoR (Version of Record)

Published in

Nature Communications

Publisher

Nature Publishing Group

eissn

2041-1723

Available date

2016-11-09

Publisher version

http://www.nature.com/articles/ncomms10023

Language

en

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