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.
Bibliographical noteFunding 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.
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.
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Copyright 2018 Elsevier B.V., All rights reserved.
- kidney function
- glomerular filtration rate
- eGFR (kidney function)
- cell types
- biological pathways
- chromatin state mapping