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

Cristian Pattaro, Alexander Teumer, Mathias Gorski, Audrey Y. Chu, Man Li, Vladan Mijatovic, Maija Garnaas, Adrienne Tin, Rossella Sorice, Yong Li, Daniel Taliun, Matthias Olden, Meredith C. Foster, Qiong Yang, Ming Huei Chen, Tune H. Pers, Andrew D. Johnson, Yi An Ko, C. Fuchsberger, Bamidele O. TayoMike A. Nalls, Mary F. Feitosa, Aaron Isaacs, Abbas Dehghan, Adamo Pio D'adamo, Adebowale Adeyemo, Aida Karina Dieffenbach, Alan B. Zonderman, Ilja M. Nolte, Peter J. Van Der Most, Alan F. Wright, Alan R. Shuldiner, Alanna C. Morrison, Albert Hofman, Albert V. Smith, Albert W. Dreisbach, Andre Franke, Andre G. Uitterlinden, Andres Metspalu, Anke Tönjes, Antonio Lupo, Antonietta Robino, Åsa Johansson, Ayse Demirkan, Barbara Kollerits, Barry I. Freedman, Belen Ponte, Ben A. Oostra, Bernhard Paulweber, Bernhard K. Krämer, Braxton D. Mitchell, Brendan Buckley, Carmen A. Peralta, Caroline Hayward, Catherine Helmer, Charles N. Rotimi, Christian M. Shaffer, Christian Müller, Cinzia Sala, Cornelia M. Van Duijn, Aude Saint-Pierre, Daniel Ackermann, Daniel Shriner, Daniela Ruggiero, Daniela Toniolo, Yingchang Lu, L. Soldati, Darina Czamara, David Ellinghaus, David S. Siscovick, Douglas Ruderfer, Christian Gieger, Harald Grallert, Elena Rochtchina, Elizabeth J. Atkinson, Elizabeth G. Holliday, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, Federico Murgia, Fernando Rivadeneira, Florian Ernst, Florian Kronenberg, Frank B. Hu, Gerjan J. Navis, Gary C. Curhan, Georg Ehret, Georg Homuth, Stefan Coassin, Gian Andri Thun, Giorgio Pistis, Giovanni Gambaro, Giovanni Malerba, Grant W. Montgomery, Gudny Eiriksdottir, Gunnar Jacobs, Guo Li, H. Erich Wichmann, Harry Campbell, Helena Schmidt, Henri Wallaschofski, Henry Völzke, Hermann Brenner, Heyo K. Kroemer, Holly Kramer, Honghuang Lin, Irene Mateo Leach, Ian Ford, Idris Guessous, Igor Rudan, Inga Prokopenko, Ingrid B. Borecki, Iris M. Heid, Ivana Kolčić, Ivana Persico, J. 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Cooper, Anna Maria Corsi, Marcus Dörr, Santosh Dahgam, John Danesh, George Davey Smith, Ian N M Day, Panos Deloukas, Matthew Denniff, Anna Dominiczak, Yanbin Dong, Ayo Doumatey, Paul Elliott, Roberto Elosua, Jeanette Erdmann, Susana Eyheramendy, Martin Farrall, Cristiano Fava, Terrence Forrester, F. Gerald Fowkes, Ervin R. Fox, Timothy M. Frayling, Pilar Galan, Santhi K. Ganesh, Melissa Garcia, Tom R. Gaunt, Nicole L. Glazer, Min Jin Go, Anuj Goel, Jürgen Gräßler, Diederick Grobbee, Leif Groop, Simonetta Guarrera, Xiuqing Guo, David Hadley, Anders Hamsten, Bok Ghee Han, Rebecca Hardy, Anna Liisa Hartikainen, Simon Heath, S. Heckbert, B. Hedblad, Serge Hercberg, Dena G. Hernandez, Andrew A. Hicks, Gina Hilton, A. Hingorani, Judith A. Hoffman Bolton, Jemma C. Hopewell, Philip J. Howard, S. E. Humphries, Steven C. Hunt, Kristian Hveem, M. Arfan Ikram, Muhammad Islam, Naoharu Iwai, Marjo Riitta Jarvelin, Anne U. Jackson, T. H. Jafar, Charles S. Janipalli, Toby Johnson, Sekar Kathiresan, Kay Tee Khaw, Hyung Lae Kim, Sanjay Kinra, Yoshikuni Kita, Mika Kivimaki, Jaspal S. Kooner, M. J Kranthi Kumar, Diana Kuh, Smita R. Kulkarni, Meena Kumari, Johanna Kuusisto, Tatiana Kuznetsova, Markku Laakso, Maris Laan, Jaana Laitinen, Edward G. Lakatta, Carl D. Langefeld, Martin G. Larson, Mark Lathrop, Debbie A. Lawlor, Robert Lawrence, Jong Young Lee, Nanette R. Lee, Daniel Levy, Yali Li, Will Longstreth, Jian'an Luan, Gavin Lucas, Barbara Ludwig, Massimo Mangino, K. Radha Mani, Michael G. Marmot, Francesco U S Mattace-Raso, G. Matullo, Wendy L. McArdle, Colin A. McKenzie, Thomas Meitinger, Olle Melander, Pierre Meneton, James Meschia, Tetsuro Miki, Yuri Milaneschi, Karen L. Mohlke, Vincent Mooser, Mario A. Morken, R. Morris, Thomas H. Mosley, Samer S. Najjar, Narisu Narisu, Christopher Newton-Cheh, Khanh Dung Hoang Nguyen, Peter Nilsson, Fredrik Nyberg, Christopher J. 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Swift, Yasuharu Tabara, E. Shyong Tai, Philippa J. Talmud, Andrew Taylor, J. Terzic, Dag S. Thelle, Martin D. Tobin, Maciej Tomaszewski, Vikal Tripathy, Jaakko Tuomilehto, I. Tzoulaki, Manuela Uda, Hirotsugu Ueshima, Cuno S P M Uiterwaal, Satoshi Umemura, Pim van der Harst, Yvonne T. Van Der Schouw, Wiek H. Van Gilst, Erkki Vartiainen, Ramachandran S. Vasan, Gudrun Veldre, Germaine C. Verwoert, Margus Viigimaa, D. G. Vinay, Paolo Vineis, Benjamin F. Voight, Peter Vollenweider, Lynne E. Wagenknecht, Louise V. Wain, Xiaoling Wang, Thomas J. Wang, Nicholas J. Wareham, H. Watkins, Alan B. Weder, P. Whincup, Kerri L. Wiggins, J. C M Witteman, Andrew Wong, Ying Wu, Chittaranjan S. Yajnik, Jie Yao, J. H. Young, Diana Zelenika, Guangju Zhai, Weihua Zhang, Feng Zhang, Jing Hua Zhao, Haidong Zhu, Xiaofeng Zhu, Paavo Zitting, Ewa Zukowska-Szczechowska, Yukinori Okada, Jer Yuarn Wu, Dongfeng Gu, Fumihiko Takeuchi, Atsushi Takahashi, Shiro Maeda, Tatsuhiko Tsunoda, Peng Chen, Su Chi Lim, Tien Yin Wong, Jianjun Liu, Terri L. Young, Tin Aung, Yik Ying Teo, Young Jin Kim, Daehee Kang, Chien Hsiun Chen, Fuu Jen Tsai, Li Ching Chang, S. J Cathy Fann, Hao Mei, James E. Hixson, Shufeng Chen, Tomohiro Katsuya, Masato Isono, Eva Albrecht, Kazuhiko Yamamoto, Michiaki Kubo, Yusuke Nakamura, Naoyuki Kamatani, Norihiro Kato, Jiang He, Yuan Tsong Chen, Toshihiro Tanaka, Muredach P. Reilly, Heribert Schunkert, Themistocles L. Assimes, A. Hall, Christian Hengstenberg, Inke R. Konig, Reijo Laaksonen, Ruth McPherson, John R. Thompson, Unnur Thorsteinsdóttir, Andreas Ziegler, Devin Absher, Li Chen, L. Adrienne Cupples, Eran Halperin, Mingyao Li, Kiran Musunuru, Michael Preuss, Arne Schillert, Gudmar Thorleifsson, George A. Wells, Hilma Holm, Robert Roberts, Alexandre F R Stewart, Stephen P. Fortmann, Alan Go, Mark Hlatky, Carlos Iribarren, Joshua W. Knowles, Richard M. Myers, Thomas Quertermous, Steven Sidney, Neil Risch, Hua Tang, Stefan Blankenberg, Renate B. Schnabel, Christoph Sinning, Karl J. Lackner, Laurence Tiret, Viviane Nicaud, F. Cambien, Christoph Bickel, Hans J. Rupprecht, Claire Perret, Carole Proust, Thomas Münzel, Maja Barbalic, Ida Yii Der Chen, Serkalem Demissie-Banjaw, Aaron R. Folsom, Thomas Lumley, Kristin Marciante, Kent D. Taylor, Kelly A. Volcik, Solveig Gretarsdottir, Jeffrey R. 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Balmforth, Stephen G. Ball, Laura R. Loehr, Wayne D. Rosamond, Emelia J. Benjamin, Talin Haritunians, David J. Couper, Joanne M. Murabito, Ying A. Wang, Bruno H C Stricker, Patricia P. Chang, James T. Willerson, Stephan B. Felix, Norbert Watzinger, Jayashri Aragam, Robert Zweiker, Lars Lind, Richard J. Rodeheffer, Karin Halina Greiser, Jaap Deckers, Jan Stritzke, Erik Ingelsson, Iftikhar J. Kullo, Johannes Haerting, Thorsten Reffelmann, Margaret M. Redfield, Karl Werdan, Gary F. Mitchell, Donna K. Arnett, John S. Gottdiener, Maria Blettner, Nele Friedrich, Peter Kovacs, Philipp S. Wild, Philippe Froguel, Rainer Rettig, Reedik Mägi, Reiner Biffar, Reinhold Schmidt, R. P. Middelberg, Robert J. Carroll, Brenda W. Penninx, Rodney J. Scott, Ronit Katz, Sanaz Sedaghat, Sarah H. Wild, Sharon L R Kardia, Sheila Ulivi, Shih Jen Hwang, Stefan Enroth, Stefan Kloiber, Stella Trompet, Benedicte Stengel, Stephen J. Hancock, Stephen T. Turner, Sylvia E. Rosas, Sylvia Stracke, Tamara B. Harris, Tanja Zeller, Tatijana Zemunik, Terho Lehtimäki, Thomas Illig, Thor Aspelund, Tiit Nikopensius, Tõnu Esko, Toshiko Tanaka, Ulf Gyllensten, Uwe Völker, Valur Emilsson, Veronique Vitart, Ville Aalto, Vilmundur Gudnason, Vincent Chouraki, Wei Min Chen, Wilmar Igl, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Ruth J F Loos, Yongmei Liu, Harold Snieder, Peter P. Pramstaller, Afshin Parsa, Jeffrey R. O'Connell, Katalin Susztak, Pavel Hamet, Johanne Tremblay, Ian H. De Boer, Carsten A. Böger, Wolfram Goessling, Daniel I. Chasman, Anna Köttgen, W. H Linda Kao, Caroline S. Fox

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number10023
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Jan 21 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

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