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 Foster, Qiong Yang, Ming Huei Chen, Tune H. Pers, Andrew D. Johnson, Yi An Ko, Christian Fuchsberger, Bamidele TayoMichael 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, Andre Franke, Andre G. Uitterlinden, Andres Metspalu, Anke Tonjes, 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 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 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, George B. 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, I. Mateo Leach, Ian Ford, Idris Guessous, Igor Rudan, Inga Prokopenko, Ingrid Borecki, Iris M. Heid, Ivana Kolcic, 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, Loic 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 A. McEvoy, Mark Woodward, Martin Adam, Massimiliano Cocca, Matthias Nauck, Medea Imboden, Melanie Waldenberger, Menno Pruijm, Marie Metzger, Michael Stumvoll, Michele K. Evans, Michele 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 Raitakari, Omri Gottesman, Oscar H. Franco, Ozren Polasek, Paolo Gasparini, Patricia B. Munroe, Paul M. Ridker, Paul Mitchell, Paul Muntner, Christa Meisinger, Johannes H. Smit, ICBP Consortium, AGEN Consortium, CARDIOGRAM, CHARGe-Heart Failure Group, ECHOGen Consortium, Peter Kovacs, Philipp Wild, Philippe Froguel, Rainer Rettig, Reedik Mägi, Reiner Biffar, Reinhold Schmidt, Rita P.S. Middelberg, Robert J. Carroll, Brenda Penninx, Rodney 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 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 Kottgen, W.H. Linda Kao, Caroline S. Fox

Research output: Contribution to journalArticlepeer-review

236 Citations (Scopus)

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
Number of pages19
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 21 Jan 2016
Externally publishedYes

Bibliographical note

Funding Information:
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.

Funding Information:
168Center for Statistical Genetics, Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, Michigan 48103, USA. 169Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599, USA. 170Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. 171Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. 172Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. 173Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 174Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. 175Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze (ASF), 50125 Florence, Italy. 176Département de Génétique Médicale, Université de Lausanne, Lausanne 1015, Switzerland. 177Pathology and Laboratory Medicine, University of Western Australia, 6009 Crawley, Western Australia, Australia. 178Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA. 179Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle 98195, Washington, USA. 180National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. 181Department of Medicine III, Medical Faculty Carl Gustav Carus at the Technical University of Dresden, Dresden 01307, Germany. 182Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA, The Netherlands. 183Leibniz-Institute for Arteriosclerosis Research, Department of Molecular Genetics of Cardiovascular Disease, University of Münster, Münster, Germany. 184University Hospital Münster, Internal Medicine D, Münster, Germany. 185Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK. 186Clinical Pharmacology Unit, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK. 187Department of Health Sciences, University of Leicester, University Rd, Leicester LE1 7RH, UK. 188Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. 189Clinical Pharmacology and The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. 190Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK. 191Centre for Cellular and Molecular Biology (CCMB), Council of Scientific and Industrial Research (CSIR), Uppal Road, Hyderabad 500 007, India. 192University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA.

Publisher Copyright:
© 2016, Nature Publishing Group. All rights reserved.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • kidney function
  • glomerular filtration rate
  • eGFR (kidney function)
  • loci
  • cell types
  • biological pathways
  • chromatin state mapping

Fingerprint

Dive into the research topics of 'Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function'. Together they form a unique fingerprint.

Cite this