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

Authors: 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, Christian Fuchsberger, Bamidele O. Tayo, Michael A. Nalls, Mary F. Feitosa, Aaron Isaacs, Abbas Dehghan, 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, André Franke, André G. Uitterlinden, Andres Metspalu, Anke Tönjes, Antonio Lupo, Antonietta Robino, Åsa Johansson, Ayşe Demirkan, Barbara Kollerits, Barry I. Freedman, Belén Ponte, Ben A. Oostra, Bernhard Paulweber, Bernhard K. Krämer, Braxton D. Mitchell, Brendan M. 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, Daniele Cusi, Darina Czamara, David Ellinghaus, David S. Siscovick, Douglas M. Ruderfer, Christian Gieger, Harald Grallert, Elena Rochtchina, Elizabeth J. Atkinson, Elizabeth G. Holliday, Eric Boerwinkle, Erika Salvi, Erwin P. Böttinger, Federico Murgia, Fernando Rivadeneira, Florian Ernst, Florian Kronenberg, Frank B. Hu, Gerjan Navis, Gary C. Curhan, G. Ehret, Georg Homuth, Stefan Coassin, Gian Andri Thun, Giorgio Pistis, Giovanni Gambaro, Giovanni Malerba, Grant W. Montgomery, Guðný Eiríksdóttir, Gunnar Jacobs, Li Guo, 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. Wouter Jukema, James F. Wilson, Janine F. Felix, Jasmin Divers, Jean‐Charles Lambert, Jeanette M. Stafford, Jean-Michel Gaspoz, Jennifer A. Smith, Jessica D. Faul, Jie Jin Wang, Jingzhong Ding, Joel N. Hirschhorn, John Attia, John B. Whitfield, John Chalmers, Jorma Viikari, Josef Coresh, Joshua C. Denny, Juha Karjalainen, Jyotika K. Fernandes, Karlhans Endlich, Katja Butterbach, Keith L. Keene, Kurt Lohman, Laura Portas, Lenore J. Launer, Leo‐Pekka Lyytikäinen, Loïc Yengo, Lude Franke, Luigi Ferrucci, Lynda M. Rose, Lyudmyla Kedenko, Madhumathi Rao, Maksim Struchalin, Marcus E. Kleber, Margherita Cavalieri, Margot Haun, Marilyn C. Cornelis, Marina Ciullo, Mario Pirastu, Mariza de Andrade, Mark McEvoy, Mark Woodward, Martin Adam, Massimiliano Cocca, Matthias Nauck, Medea Imboden, Mélanie Waldenberger, Menno Pruijm, Marie Metzger, Michael Stümvoll, Michele K. Evans, Michèle M. Sale, Mika Kähönen, Mladen Boban, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nabila Bouatia‐Naji, Nicholas G. Martin, Nick Hastie, Nicole Probst‐Hensch, Nicole Soranzo, Olivier Devuyst, Olli T. Raitakari, Omri Gottesman, Oscar H. Franco, Ozren Polašek, Paolo Gasparini, Patricia B. Munroe, Paul M. Ridker, Paul Mitchell, Paul Muntner, Christa Meisinger, Johannes H. Smit, Gonçalo R. Abecasis, Linda S. Adair, M Alexander, David Altshuler, Najaf Amin, Dan E. Arking, Pankaj Arora, Yurii S. Aulchenko, Stephan J. L. Bakker, Stefania Bandinelli, Inês Barroso, J. Beckmann, John Beilby, Richard N. Bergman, Sven Bergmann, Joshua C. Bis, Michael Boehnke, Lori L. Bonnycastle, Stefan R. Bornstein, Michiel L. Bots, Jennifer L. Bragg‐Gresham, Stefan-Martin Brand, Eva Brand, Peter S. Braund, Morris J. Brown, Paul R. Burton, Juan P. Casas, Mark J. Caulfield, Aravinda Chakravarti, John C. Chambers, Giriraj R. Chandak, Yen-Pei C. Chang, Fadi J. Charchar, Nish Chaturvedi, Yoon Shin Cho, Robert Clarke, Francis S. Collins, Rory Collins, John Connell, Jackie A. Cooper, Matthew N. Cooper, Richard S. Cooper, A. Corsi, Marcus Dörr, Santosh Dahgam, John Danesh, George Davey Smith, Ian N.M. Day, Panos Deloukas, Matthew Denniff, Anna F. Dominiczak, Yanbin Dong, Ayo P. Doumatey, Paul Elliott, Roberto Elosúa, Jeanette Erdmann, S. Eyheramendy, Martin Farrall, Cristiano Fava, Terrence Forrester, F.G.R. Fowkes, Ervin R. Fox, Timothy M. Frayling, Pilar Galán, Santhi K. Ganesh, Melissa García, Tom R. Gaunt, Nicole L. Glazer, Min Jin Go, Anuj Goel, Jürgen Gräßler, Diederick E. Grobbee, Leif Groop, Simonetta Guarrera, Xiuqing Guo, David Hadley, Anders Hamsten, Bok-Ghee Han, Rebecca Hardy, Anna-Liisa Hartikainen, Simon Heath, Susan R. Heckbert, Bo Hedblad, Serge Herçberg, Dena Hernández, Andrew A. Hicks, Gina M. Hilton, Aroon D. Hingorani, Judith A. Hoffman Bolton, Jemma C. Hopewell, Philip Howard, Steve E. Humphries, Steven C. Hunt, Kristian Hveem, M. Arfan Ikram, Saiful Islam, Naoharu Iwai, Marjo‐Riitta Järvelin, Anne Jackson, Tazeen H. Jafar, Charles S. Janipalli, Toby Johnson, Sekar Kathiresan, Kay‐Tee Khaw, Hyung‐Lae Kim, Sanjay Kinra, Yoshikuni Kita, Mika Kivimäki, Jaspal S. Kooner, G Anil Kumar, Diana Kuh, Smita 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, Sang Lee, Daniel Levy, Yali Li, W. T. Longstreth, Jian’an Luan, Gavin Lucas, Barbara Ludwig, Massimo Mangino, K. Radha Mani, Michael Marmot, Francesco Mattace‐Raso, Giuseppe Matullo, Wendy L. McArdle, Colin A. McKenzie, Thomas Meitinger, Olle Melander, Pierre Meneton, James F. Meschia, Tetsuro Miki, Yuri Milaneschi, Karen L. Mohlke, Vincent Mooser, Mario A. Morken, Richard Morris, Thomas H. Mosley, Samer S. Najjar, Narisu Narisu, Christopher Newton‐Cheh, Khanh-Dung H. Nguyen, Peter M. Nilsson, Fredrik Nyberg, Christopher J. O’Donnell, Toshio Ogihara, Takayoshi Ohkubo, Tomonori Okamura, RickTwee-Hee Ong, Halit Ongen, N. Charlotte Onland‐Moret, Paul F. O’Reilly, Elin Org, Marco Orrù, Walter Palmas, Jutta Palmen, Lyle J. Palmer, Nicholette D. Palmer, Alex Parker, John F. Peden, Leena Peltonen, Markus Perola, Vasyl Pihur, Carl G. P. Platou, Andrew Plump, Dorairaj Prabhakaran, Bruce M. Psaty, Leslie J. Raffel, D. C. Rao, Asif Rasheed, Fulvio Ricceri, Kenneth Rice, Annika Rosengren, Jerome I. Rotter, Megan E. Rudock, Siim Sõber, Tunde Salako, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Steven M. Schwartz, Peter Schwarz, Laura J. Scott, James Scott, Angelo Scuteri, Joban Sehmi, Mark Seielstad, Sudha Seshadri, Pankaj Sharma, Sue Shaw‐Hawkins, Gang Shi, Nick Shrine, Eric J.G. Sijbrands, Xueling Sim, Andrew B. Singleton, Marketa Sjögren, Nicholas L. Smith, María Soler Artigas, Tim D. Spector, Jan A. Staessen, Alena Stančáková, Nanette Steinle, David P. Strachan, Heather M. Stringham, Yan V. Sun, Amy J. Swift, Yasuharu Tabara, E Shyong Tai, Philippa J. Talmud, Andrew M. Taylor, Janoš Terzić, Dag S. Thelle, Martin D. Tobin, Maciej Tomaszewski, Vikal Tripathy, Jaakko Tuomilehto, Ioanna 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, Péter Vollenweider, Lynne E. Wagenknecht, Louise V. Wain, Xiaoling Wang, Thomas J. Wang, Nicholas J. Wareham, Hugh Watkins, Alan B. Weder, Peter H. Whincup, Kerri L. Wiggins, Jacqueline C.M. Witteman, Andrew Wong, Ying Wu, Chittaranjan S. Yajnik, Jie Yao, J. 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Adrienne Cupples, Eran Halperin, Mingyao Li, Kiran Musunuru, Michael Preuß, Arne Schillert, Guðmar Þorleifsson, George A. Wells, Hilma Hólm, Robert Roberts, Alexandre F.R. Stewart, Stephen P. Fortmann, Alan S. Go, Mark A. Hlatky, Carlos Iribarren, Joshua W. Knowles, Richard H. Myers, Thomas Quertermous, Steven Sidney, Neil Risch, Hua Tang, Stefan Blankenberg, Renate B. Schnabel, Christoph Sinning, Karl J. Lackner, Laurence Tiret, Viviane Nicaud, François Cambien, Christoph Bickel, Hans J. Rupprecht, Claire Perret, Carole Proust, Thomas F. Münzel, Maja Barbalić, Ida Yii-Der Chen, Serkalem Demissie-Banjaw, Aaron R. Folsom, Thomas Lumley, Kristin D. Marciante, Kent D. Taylor, Kelly A. Volcik, Sólveig Grétarsdóttir, Jeffrey R. Gulcher, Augustine Kong, Kāri Stefánsson, Guðmundur Þorgeirsson, Karl Andersen, Marcus Fischer, Anika Großhennig, Patrick Linsel‐Nitschke, Klaus Stark, Stefan Schreiber, Zouhair Aherrahrou, Petra Bruse, Angela Doering, Norman Klopp, Patrick Diemert, Christina Loley, Anja Medack, Janja Nahrstedt, Annette Peters, Arnika Kathleen Wagner, Christina Willenborg, Bernhard Böhm, Harald Dobnig, Tanja B. Grammer, Michael M. Hoffmann, Andreas Meinitzer, Bernhard R. Winkelmann, Stefan Pilz, Wilfried Renner, Hubert Scharnagl, Tatjana Stojaković, Andreas Tomaschitz, Karl Winkler, Candace Guiducci, Noël P. Burtt, Stacey Gabriel, Sonny Dandona, Olga Jarinova, Liming Qu, Robert Wilensky, William Matthai, Håkon Håkonarson, Joe Devaney, Mary Susan Burnett, Augusto D. Pichard, Kenneth M. Kent, Lowell Satler, Joseph Lindsay, Ron Waksman, Christopher W. Knouff, Dawn Waterworth, Max Walker, Stephen E. Epstein, Daniel J. Rader, Christopher P. Nelson, Benjamin J. Wright, Anthony J. Balmforth, Stephen G. Ball, CHARGe-Heart Failure Group, Laura R. Loehr, Wayne D. Rosamond, Emelia J. Benjamin, Talin Haritunians, David Couper, Joanne M. Murabito, Ying A. Wang, Bruno H. 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 W. 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, Péter Kovács, Philipp S. Wild, Philippe Froguel, Rainer Rettig, Reedik Mägi, Reiner Biffar, Reinhold Schmidt, Rita P. S. Middelberg, Robert J. Carroll, Brenda W.J.H. 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, Bénédicte Stengel, Stephen 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, Véronique Vitart, Ville Aalto, Vilmundur Guðnason, Vincent Chouraki, Wei‐Min Chen, Wilmar Igl, Winfried März, Wolfgang Köenig, Wolfgang Lieb, Ruth J. F. Loos, Ching‐Ti Liu, Harold Snieder, Peter P. Pramstaller, Afshin Parsa, Jeffrey R. O’Connell, Katalin Suszták, 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 - Nature Communications 2016 cited by 536

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.