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

Pattaro, C. et al. (2016) Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nature Communications, 7, 10023. (doi:10.1038/ncomms10023) (PMID:26831199) (PMCID:PMC4735748)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ford, Professor Ian and Dominiczak, Professor Anna
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., 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.’a., 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. J., Ogihara, T., Ohkubo, T., Okamura, T., Ong, R.-H., Ongen, H., Onland-Moret, N. C., O’Reilly, P. F., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, L. J., Palmer, N. D., Parker, A. N., Peden, J. F., Peltonen, L., Perola, M., Pihur, V., Platou, C. G. P., Plump, A., Prabhakaran, D., Psaty, B. M., Raffel, L. J., Rao, D. C., Rasheed, A., Ricceri, F., Rice, K. M., Rosengren, A., Rotter, J. I., Rudock, M. E., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, N. J., Schwartz, S. M., Schwarz, P. E. H., Scott, L. J., Scott, J., Scuteri, A., Sehmi, J. S., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, N. R. G., Sijbrands, E. J. G., Sim, X., Singleton, A., Sjögren, M., Smith, N. L., Artigas, M. S., Spector, T. D., Staessen, J. A., Stancakova, A., Steinle, N. I., Strachan, D. P., Stringham, H. M., Sun, Y. V., Swift, A. J., Tabara, Y., Tai, E.-S., Talmud, P. J., Taylor, A., Terzic, J., Thelle, D. S., Tobin, M. 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., 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., 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., 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., 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., and Fox, C. S.
Subjects:R Medicine > R Medicine (General)
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Nature Communications 7: 10023
Publisher Policy:Reproduced under a Creative Commons License

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