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

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S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih-Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thomas, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei-Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O’Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, de Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, Fox, Caroline S.·2016·Nature Communications

DOI 10.1038/ncomms10023

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Abstract

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.

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Authors: Pattaro, C., Teumer, A., Gorski, M., Chu, A. Y., Li, M., Mijatovic, V., Garnaas, M., Tin, A., Sorice, R., Li, Y., Taliun, D., Olden, M., Foster, M., Yang, Q., Chen, M.-H., Pers, T. H., Johnson, A. D., Ko, Y.-A., Fuchsberger, C., Tayo, B., Nalls, M., Feitosa, M. F., Isaacs, A., Dehghan, A., d’Adamo, P., Adeyemo, A., Dieffenbach, A. K., Zonderman, A. B., Nolte, I. M., van der Most, P. J., Wright, A. F., Shuldiner, A. R., Morrison, A. C., Hofman, A., Smith, A. V., Dreisbach, A. W., Franke, A., Uitterlinden, A. G., Metspalu, A., Tonjes, A., Lupo, A., Robino, A., Johansson, Å., Demirkan, A., Kollerits, B., Freedman, B. I., Ponte, B., Oostra, B. A., Paulweber, B., Krämer, B. K., Mitchell, B. D., Buckley, B. M., Peralta, C. A., Hayward, C., Helmer, C., Rotimi, C. N., Shaffer, C. M., Müller, C., Sala, C., van Duijn, C. M., Saint-Pierre, A., Ackermann, D., Shriner, D., Ruggiero, D., Toniolo, D., Lu, Y., Cusi, D., Czamara, D., Ellinghaus, D., Siscovick, D. S., Ruderfer, D., Gieger, C., Grallert, H., Rochtchina, E., Atkinson, E. J., Holliday, E. G., Boerwinkle, E., Salvi, E., Bottinger, E. P., Murgia, F., Rivadeneira, F., Ernst, F., Kronenberg, F., Hu, F. B., Navis, G. J., Curhan, G. C., Ehret, G. B., Homuth, G., Coassin, S., Thun, G.-A., Pistis, G., Gambaro, G., Malerba, G., Montgomery, G. W., Eiriksdottir, G., Jacobs, G., Li, G., Wichmann, H.-E., Campbell, H., Schmidt, H., Wallaschofski, H., Völzke, H., Brenner, H., Kroemer, H. K., Kramer, H., Lin, H., Leach, I. M., Ford, I., Guessous, I., Rudan, I., Prokopenko, I., Borecki, I., Heid, I. M., Kolcic, I., Persico, I., Jukema, J. W., Wilson, J. F., Felix, J. F., Divers, J., Lambert, J.-C., Stafford, J. M., Gaspoz, J.-M., Smith, J. A., Faul, J. D., Wang, J. J., Ding, J., Hirschhorn, J. N., Attia, J., Whitfield, J. B., Chalmers, J., Viikari, J., Coresh, J., Denny, J. C., Karjalainen, J., Fernandes, J. K., Endlich, K., Butterbach, K., Keene, K. L., Lohman, K., Portas, L., Launer, L. J., Lyytikäinen, L.-P., Yengo, L., Franke, L., Ferrucci, L., Rose, L. M., Kedenko, L., Rao, M., Struchalin, M., Kleber, M. E., Cavalieri, M., Haun, M., Cornelis, M. C., Ciullo, M., Pirastu, M., de Andrade, M., McEvoy, M. A., Woodward, M., Adam, M., Cocca, M., Nauck, M., Imboden, M., Waldenberger, M., Pruijm, M., Metzger, M., Stumvoll, M., Evans, M. K., Sale, M. M., Kähönen, M., Boban, M., Bochud, M., Rheinberger, M., Verweij, N., Bouatia-Naji, N., Martin, N. G., Hastie, N., Probst-Hensch, N., Soranzo, N., Devuyst, O., Raitakari, O., Gottesman, O., Franco, O. H., Polasek, O., Gasparini, P., Munroe, P. B., Ridker, P. M., Mitchell, P., Muntner, P., Meisinger, C., Smit, J. H., ICBP Consortium, Abecasis, G. R., Adair, L. S., Alexander, M., Altshuler, D., Amin, N., Arking, D. E., Arora, P., Aulchenko, Y., Bakker, S. J. L., Bandinelli, S., Barroso, I., Beckmann, J. S., Beilby, J. P., Bergman, R. N., Bergmann, S., Bis, J. C., Boehnke, M., Bonnycastle, L. L., Bornstein, S. R., Bots, M. L., Bragg-Gresham, J. L., Brand, S.-M., Brand, E., Braund, P. S., Brown, M. J., Burton, P. R., Casas, J. P., Caulfield, M. J., Chakravarti, A., Chambers, J. C., Chandak, G. R., Chang, Y.-P. C., Charchar, F. J., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, F. S., Collins, R., Connell, J. M., Cooper, J. A., Cooper, M. N., Cooper, R. S., Corsi, A. M., Dörr, M., Dahgam, S., Danesh, J., Smith, G. D., Day, I. N. M., Deloukas, P., Denniff, M., Dominiczak, A. F., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, F. G. R., Fox, E. R., Frayling, T. M., Galan, P., Ganesh, S. K., Garcia, M., Gaunt, T. R., Glazer, N. L., Go, M. J., Goel, A., Grässler, J., Grobbee, D. E., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, B.-G., Hardy, R., Hartikainen, A.-L., Heath, S., Heckbert, S. R., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, A. A., Hilton, G., Hingorani, A. D., Bolton, J. A. H., Hopewell, J. C., Howard, P., Humphries, S. E., Hunt, S. C., Hveem, K., Ikram, M. A., Islam, M., Iwai, N., Jarvelin, M.-R., Jackson, A. U., Jafar, T. H., Janipalli, C. S., Johnson, T., Kathiresan, S., Khaw, K.-T., Kim, H.-L., Kinra, S., Kita, Y., Kivimaki, M., Kooner, J. S., Kumar, M. J. K., Kuh, D., Kulkarni, S. R., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, E. G., Langefeld, C. D., Larson, M. G., Lathrop, M., Lawlor, D. A., Lawrence, R. W., Lee, J.-Y., Lee, N. R., Levy, D., Li, Y., Longstreth, W. T., Luan, J., Lucas, G., Ludwig, B., Mangino, M., Mani, K. R., Marmot, M. G., Mattace-Raso, F. U. S., Matullo, G., McArdle, W. L., McKenzie, C. A., Meitinger, T., Melander, O., Meneton, P., Meschia, J. F., Miki, T., Milaneschi, Y., Mohlke, K. L., Mooser, V., Morken, M. A., Morris, R. W., Mosley, T. H., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, K.-D. H., Nilsson, P., Nyberg, F., O’Donnell, C. 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D., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, C. S. P. M., Umemura, S., van der Harst, P., van der Schouw, Y. T., van Gilst, W. H., Vartiainen, E., Vasan, R. S., Veldre, G., Verwoert, G. C., Viigimaa, M., Vinay, D. G., Vineis, P., Voight, B. F., Vollenweider, P., Wagenknecht, L. E., Wain, L. V., Wang, X., Wang, T. J., Wareham, N. J., Watkins, H., Weder, A. B., Whincup, P. H., Wiggins, K. L., Witteman, J. C. M., Wong, A., Wu, Y., Yajnik, C. S., Yao, J., Young, J. H., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, J. H., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., AGEN Consortium, Okada, Y., Wu, J.-Y., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, S.-C., Wong, T.-Y., Liu, J., Young, T. L., Aung, T., Teo, Y.-Y., Kim, Y. J., Kang, D., Chen, C.-H., Tsai, F.-J., Chang, L.-C., Fann, S. J. C., Mei, H., Hixson, J. E., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, Y.-T., Tanaka, T., CARDIOGRAM, Reilly, M. P., Schunkert, H., Assimes, T. L., Hall, A., Hengstenberg, C., König, I. R., Laaksonen, R., McPherson, R., Thompson, J. R., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, L. A., Halperin, E., Li, M., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, G. A., Holm, H., Roberts, R., Stewart, A. F. R., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, K. J., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, H. J., Perret, C., Proust, C., Münzel, T. F., Barbalic, M., Chen, I. Y.-D., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, K. D., Volcik, K., Gretarsdottir, S., Gulcher, J. R., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, A. K., Willenborg, C., Böhm, B. O., Dobnig, H., Grammer, T. B., Hoffmann, M. M., Meinitzer, A., Winkelmann, B. R., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, S. B., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, H. H., Devaney, J., Burnett, M. S., Pichard, A. D., Kent, K. M., Satler, L., Lindsay, J. M., Waksman, R., Knouff, C. W., Waterworth, D. M., Walker, M. C., Epstein, S. E., Rader, D. J., Nelson, C. P., Wright, B. J., Balmforth, A. J., Ball, S. G., CHARGe-Heart Failure Group, Loehr, L. R., Rosamond, W. D., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, Y. A., Stricker, B. H., Chang, P. P., Willerson, J. T., ECHOGen Consortium, Felix, S. B., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, R. J., Greiser, K. H., Deckers, J. W., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, M. M., Werdan, K., Mitchell, G. F., Arnett, D. K., Gottdiener, J. S., Blettner, M., Friedrich, N., Kovacs, P., Wild, P. S., Froguel, P., Rettig, R., Mägi, R., Biffar, R., Schmidt, R., Middelberg, R. P. S., Carroll, R. J., Penninx, B. W., Scott, R. J., Katz, R., Sedaghat, S., Wild, S. H., Kardia, S. L. R., Ulivi, S., Hwang, S.-J., Enroth, S., Kloiber, S., Trompet, S., Stengel, B., Hancock, S. J., Turner, S. T., Rosas, S. E., Stracke, S., Harris, T. B., Zeller, T., Zemunik, T., Lehtimäki, T., Illig, T., Aspelund, T., Nikopensius, T., Esko, T., Tanaka, T., Gyllensten, U., Völker, U., Emilsson, V., Vitart, V., Aalto, V., Gudnason, V., Chouraki, V., Chen, W.-M., Igl, W., März, W., Koenig, W., Lieb, W., Loos, R. J. F., Liu, Y., Snieder, H., Pramstaller, P. P., Parsa, A., O’Connell, J. R., Susztak, K., Hamet, P., Tremblay, J., de Boer, I. H., Böger, C. A., Goessling, W., Chasman, D. I., Köttgen, A., Kao, W. H. L., & Fox, C. S.
Venue: Nature Communications
Publisher: Springer Science and Business Media LLC
Published: 2016-01-21
Volume: 7
Issue: 1
Pages: 10023-10023
ISSN: 2041-1723 (ISSN-L)
DOI: 10.1038/ncomms10023
OpenAlex: W2411709723
Cited by: 517
References: 49
FWCI: 51.86
Type: journal article
Language: en
Open access: gold

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

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