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      Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

      research-article
      1 , 2 , 196 , * , 3 , 196 , 4 , 196 , 5 , 196 , 5 , 196 , 6 , 7 , 196 , 8 , 9 , 10 , 11 , 1 , 12 , 13 , 14 , 15 , 16 , 17 , 5 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 6 , 7 , 16 , 21 , 28 , 29 , 30 , 28 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 3 , 45 , 7 , 46 , 47 , 45 , 48 , 49 , 50 , 24 , 29 , 51 , 52 , 53 , 54 , 20 , 55 , 24 , 1 , 37 , 38 , 56 , 57 , 58 , 59 , 33 , 21 , 60 , 61 , 62 , 28 , 63 , 64 , 65 , 66 , 67 , 68 , 36 , 26 , 69 , 70 , 33 , 24 , 45 , 71 , 72 , 73 , 74 , 24 , 45 , 21 , 75 , 15 , 76 , 77 , German Chronic Kidney Disease Study 78 , 79 , 80 , 81 , 82 , 3 , 21 , 83 , 84 , 15 , 85 , 86 , 87 , 88 , 89 , 90 , 28 , 91 , 92 , 93 , 94 , 95 , 76 , 96 , 15 , 97 , 98 , 49 , 99 , 10 , 100 , 22 , 101 , 22 , 102 , 3 , 7 , 65 , 66 , 62 , 103 , 104 , 105 , 52 , 53 , 106 , 107 , 7 , 65 , 66 , 108 , 62 , 109 , 110 , 72 , 24 , 111 , 29 , 87 , 78 , 28 , 112 , 6 , 7 , 113 , 114 , 87 , 79 , 115 , 116 , 75 , 62 , 117 , 118 , 21 , 119 , 120 , 121 , 104 , 122 , 123 , 79 , 124 , V. A. Million Veteran Program 78 , 125 , 126 , 127 , 128 , 87 , 129 , 87 , 130 , 60 , 131 , 104 , 132 , 133 , 134 , 113 , 135 , 136 , 137 , 26 , 138 , 139 , 140 , 141 , 27 , 142 , 143 , 144 , 145 , 124 , 146 , 73 , 74 , 104 , 147 , 49 , 148 , 149 , 150 , 151 , 48 , 152 , 7 , 113 , 61 , 153 , 129 , 154 , 155 , 156 , 157 , 10 , 41 , 158 , 159 , 24 , 49 , 160 , 161 , 160 , 162 , 37 , 38 , 20 , 55 , 163 , 164 , 158 , 165 , 166 , 83 , 50 , 77 , 167 , 129 , 132 , 133 , 168 , 15 , 70 , 7 , 169 , 7 , 46 , 27 , 15 , 59 , 170 , 80 , 171 , 172 , 147 , 173 , 174 , 175 , 28 , 112 , 176 , 173 , 177 , 26 , 178 , 179 , 179 , 72 , 73 , 104 , 75 , 180 , 3 , 49 , 141 , 29 , 52 , 70 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 21 , 188 , 189 , 10 , 190 , 27 , 191 , 192 , 193 , 194 , 195 , 15 , 9 , 6 , 7 , 11 , 127 , 195 , 197 , 25 , 26 , 197 , 21 , 197 , 4 , 197 , 3 , 197 , 1 , 5 , 197 , *
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          Abstract

          Elevated serum urate levels cause gout and correlate with cardio-metabolic diseases via poorly understood mechanisms. We performed a trans-ethnic genome-wide association study of serum urate among 457,690 individuals, identifying 183 loci (147 novel) that improve prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardio-metabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci, and co-localization with gene expression in 47 tissues implicated kidney and liver as main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A trans-activated the promoter of the major urate transporter ABCG2 in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional co-regulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardio-metabolic traits.

          Editorial summary:

          A trans-ethnic genome-wide association study of serum urate levels identifies 183 loci influencing this trait. Enrichment analyses, fine mapping and co-localization with gene expression in 47 tissues implicate kidney and liver as key target organs and prioritize potential causal genes.

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          Most cited references60

          • Record: found
          • Abstract: found
          • Article: not found

          JASPAR: an open-access database for eukaryotic transcription factor binding profiles.

          The analysis of regulatory regions in genome sequences is strongly based on the detection of potential transcription factor binding sites. The preferred models for representation of transcription factor binding specificity have been termed position-specific scoring matrices. JASPAR is an open-access database of annotated, high-quality, matrix-based transcription factor binding site profiles for multicellular eukaryotes. The profiles were derived exclusively from sets of nucleotide sequences experimentally demonstrated to bind transcription factors. The database is complemented by a web interface for browsing, searching and subset selection, an online sequence analysis utility and a suite of programming tools for genome-wide and comparative genomic analysis of regulatory regions. JASPAR is available at http://jaspar. cgb.ki.se.
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            • Record: found
            • Abstract: found
            • Article: not found

            Major facilitator superfamily.

            The major facilitator superfamily (MFS) is one of the two largest families of membrane transporters found on Earth. It is present ubiquitously in bacteria, archaea, and eukarya and includes members that can function by solute uniport, solute/cation symport, solute/cation antiport and/or solute/solute antiport with inwardly and/or outwardly directed polarity. All homologous MFS protein sequences in the public databases as of January 1997 were identified on the basis of sequence similarity and shown to be homologous. Phylogenetic analyses revealed the occurrence of 17 distinct families within the MFS, each of which generally transports a single class of compounds. Compounds transported by MFS permeases include simple sugars, oligosaccharides, inositols, drugs, amino acids, nucleosides, organophosphate esters, Krebs cycle metabolites, and a large variety of organic and inorganic anions and cations. Protein members of some MFS families are found exclusively in bacteria or in eukaryotes, but others are found in bacteria, archaea, and eukaryotes. All permeases of the MFS possess either 12 or 14 putative or established transmembrane alpha-helical spanners, and evidence is presented substantiating the proposal that an internal tandem gene duplication event gave rise to a primordial MFS protein prior to divergence of the family members. All 17 families are shown to exhibit the common feature of a well-conserved motif present between transmembrane spanners 2 and 3. The analyses reported serve to characterize one of the largest and most diverse families of transport proteins found in living organisms.
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              • Record: found
              • Abstract: found
              • Article: not found

              Molecular identification of a renal urate anion exchanger that regulates blood urate levels.

              Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                29 August 2019
                02 October 2019
                October 2019
                02 April 2020
                : 51
                : 10
                : 1459-1474
                Affiliations
                [1 ]Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
                [2 ]Welch Centre for Prevention, Epidemiology and Clinical Research, Baltimore, MD, USA.
                [3 ]Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
                [4 ]Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
                [5 ]Institute of Genetic Epidemiology, Department of Biometry, Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.
                [6 ]Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
                [7 ]LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
                [8 ]Target Sciences - Genetics, GlaxoSmithKline, Collegeville, PA, USA.
                [9 ]Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
                [10 ]Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
                [11 ]Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
                [12 ]Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
                [13 ]Division of Quantitative Sciences, Department of Obstetrics & Gynecology, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN, USA.
                [14 ]Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
                [15 ]deCODE Genetics, Amgen Inc., Reykjavik, Iceland.
                [16 ]Department of Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA.
                [17 ]Genetics, Merck & Co., Inc., Kenilworth, NJ, USA.
                [18 ]Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
                [19 ]Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.
                [20 ]Institute of Genetics and Biophysics Adriano Buzzati-Traverso - CNR, Naples, Italy.
                [21 ]Eurac Research, Institute for Biomedicine (affiliated to the University of Lübeck), Bolzano, Italy.
                [22 ]Laboratory for Statistical Analysis, RIKEN Centre for Integrative Medical Sciences (IMS), Yokohama (Kanagawa), Japan.
                [23 ]Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
                [24 ]Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy.
                [25 ]Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
                [26 ]DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany.
                [27 ]Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
                [28 ]Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
                [29 ]Department of Epidemiology and Biostatistics, Faculty of Medicine, School of Public Health, Imperial College London, London, UK.
                [30 ]Institute of Public Health & Social Sciences, Khyber Medical University, Peshawar, Pakistan.
                [31 ]Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.
                [32 ]School of Health and Social Studies, Dalarna University, Falun, Sweden.
                [33 ]Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
                [34 ]Division of Nephrology, University of Washington, Seattle, WA, USA.
                [35 ]Kidney Research Institute, University of Washington, Seattle, WA, USA.
                [36 ]Cardiology, Geneva University Hospitals, Geneva, Switzerland.
                [37 ]Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
                [38 ]Swiss Institute of Bioinformatics, Lausanne, Switzerland.
                [39 ]Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
                [40 ]Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
                [41 ]Department of Biostatistics, University of Washington, Seattle, WA, USA.
                [42 ]Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy.
                [43 ]Human Genetics Centre, University of Texas Health Science Centre, Houston, Texas, USA.
                [44 ]Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [45 ]University of Trieste, Department of Medicine, Surgery and Health Sciences, Trieste, Italy.
                [46 ]Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany.
                [47 ]Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany.
                [48 ]Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
                [49 ]Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
                [50 ]Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
                [51 ]Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
                [52 ]Department of Cardiology, Ealing Hospital, Middlesex, UK.
                [53 ]Imperial College Healthcare NHS Trust, Imperial College London, London, UK.
                [54 ]MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
                [55 ]IRCCS Neuromed, Pozzilli, Italy.
                [56 ]Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland.
                [57 ]Institute of Biomedical Technologies, Italy National Research Council, Segrate (Milano), Italy.
                [58 ]Bio4Dreams - business nursery for life sciences, Bresso (Milano), Italy.
                [59 ]San Raffaele Research Institute, Milano, Italy.
                [60 ]Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands.
                [61 ]Section of Nephrology, Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
                [62 ]5th Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
                [63 ]Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
                [64 ]Institute of Physiology, University of Zurich, Zurich, Switzerland.
                [65 ]Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
                [66 ]Centre for Pediatric Research, University of Leipzig, Leipzig, Germany.
                [67 ]Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Germany.
                [68 ]Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Germany.
                [69 ]Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
                [70 ]Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
                [71 ]Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala, Sweden.
                [72 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany.
                [73 ]Institute of Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany.
                [74 ]German Center for Diabetes Research (DZD), Neuherberg, Germany.
                [75 ]QIMR Berghofer Medical Research Institute, Brisbane, Australia.
                [76 ]Icelandic Heart Association, Kopavogur, Iceland.
                [77 ]Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
                [78 ]A list of members and affiliations appears in the Supplementary Note.
                [79 ]Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
                [80 ]Montreal University Hospital Research Centre, CHUM, Montreal, QC, Canada.
                [81 ]Medpharmgene, Montreal, QC, Canada.
                [82 ]Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
                [83 ]Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria.
                [84 ]Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
                [85 ]Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Centre, Shanghai, China.
                [86 ]Shanghai Industrial Technology Institute, Shanghai, China.
                [87 ]Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
                [88 ]Department of Pediatrics, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
                [89 ]NHLBIs Framingham Heart Study, Framingham, MA, USA.
                [90 ]The Centre for Population Studies, NHLBI, Framingham, MA, USA.
                [91 ]Department of Physiology, University of Maryland School of Medicine
                [92 ]Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
                [93 ]Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
                [94 ]Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
                [95 ]Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
                [96 ]The Centre of Public Health Sciences, University of Iceland, Reykjavik, Iceland.
                [97 ]Landspitalinn University Hospital, Iceland.
                [98 ]University of Iceland, Iceland.
                [99 ]Geisinger Research, Biomedical and Translational Informatics Institute, Rockville, MD, USA.
                [100 ]Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
                [101 ]Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
                [102 ]Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
                [103 ]Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
                [104 ]DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
                [105 ]Institute of Epidemiology and Biostatistics, University of Ulm, Ulm, Germany.
                [106 ]MRC-PHE Centre for Environment and Health, 323 School of Public Health, Imperial College London, London, UK.
                [107 ]National Heart and Lung Institute, Imperial College London, London, UK.
                [108 ]Integrated Research and Treatment Centre Adiposity Diseases, University of Leipzig, Leipzig, Germany.
                [109 ]Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
                [110 ]RIKEN Centre for Integrative Medical Sciences (IMS), Yokohama (Kanagawa), Japan.
                [111 ]Division of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, USA.
                [112 ]Nuffield Department of Population Health, Oxford University, Oxford, UK.
                [113 ]The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [114 ]The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [115 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
                [116 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
                [117 ]Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
                [118 ]Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
                [119 ]Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
                [120 ]Independent Research Group Clinical Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
                [121 ]Chair of Epidemiology Ludwig- Maximilians-Universität München at UNIKA-T Augsburg, Augsburg, Germany.
                [122 ]Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
                [123 ]Institute of Human Genetics, Technische Universität München, Munich, Germany.
                [124 ]Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
                [125 ]VA Boston Healthcare System, Boston, MA, USA.
                [126 ]Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
                [127 ]Vanderbilt University Medical Centre, Division of Nephrology & Hypertension, Nashville, TN, USA.
                [128 ]Massachusetts Veterans Epidemiology Research and Information Center, VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.
                [129 ]Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
                [130 ]University of Queensland, St Lucia, Australia
                [131 ]Department of Public Health and Primary Care, Leiden University Medical Centre, Leiden, The Netherlands.
                [132 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany.
                [133 ]Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany.
                [134 ]Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
                [135 ]Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [136 ]Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
                [137 ]Data Tecnica International, Glen Echo, MD, USA.
                [138 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
                [139 ]Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, Finland.
                [140 ]Department of Cardiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
                [141 ]Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
                [142 ]Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
                [143 ]University of Maryland School of Medicine, Baltimore, MD, USA.
                [144 ]Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, Iceland.
                [145 ]Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
                [146 ]Department of Medicine, Geriatrics Section, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.
                [147 ]Institute of Genetic and Biomedical Research, National Research Council of Italy, UOS of Sassari, Li Punti (Sassari), Italy.
                [148 ]Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
                [149 ]Faculty of Medicine, University of Split, Split, Croatia.
                [150 ]Gen-info Ltd, Zagreb, Croatia.
                [151 ]Nephrology Service, Department of Specialties in Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland.
                [152 ]Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
                [153 ]Einthoven Laboratory of Experimental Vascular Research, Leiden University Medical Centre, Leiden, The Netherlands.
                [154 ]Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
                [155 ]Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
                [156 ]Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
                [157 ]Institute of Physiology, University Medicine Greifswald, Karlsburg, Germany.
                [158 ]Department of Health Sciences, University of Milan, Milano, Italy.
                [159 ]ePhood Scientific Unit, ePhood SRL, Milano, Italy.
                [160 ]Centre for Cardiovascular Prevention, First Faculty of Medicine, Department of Medicine, Charles University in Prague, Prague, Czech Republic.
                [161 ]Thomayer Hospital, Prague, Czech Republic.
                [162 ]Department of Preventive Cardiology, Thomayer Hospital, Prague, Czech Republic.
                [163 ]Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
                [164 ]Molecular Biology and Biochemistry, Gottfried Schatz Research Centre for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria.
                [165 ]Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
                [166 ]Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria.
                [167 ]Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
                [168 ]Division of Endocrinology, Nephrology and Rheumatology, University of Leipzig, Leipzig, Germany.
                [169 ]Heart Centre Leipzig, Leipzig, Germany.
                [170 ]Department of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
                [171 ]CRCHUM, Montreal, QC, Canada.
                [172 ]Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
                [173 ]Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
                [174 ]Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
                [175 ]Durrer Centre for Cardiovascular Research, The Netherlands Heart Institute, Utrecht, The Netherlands.
                [176 ]Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
                [177 ]Genomics plc, Oxford, UK.
                [178 ]Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
                [179 ]Internal Medicine, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
                [180 ]Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
                [181 ]Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
                [182 ]Department of Physiology and Biophysics, University of Mississippi Medical Centre, Jackson, MS, USA.
                [183 ]Geisinger Research, Biomedical and Translational Informatics Institute, Danville, PA, USA.
                [184 ]Kidney Health Research Institute (KHRI), Geisinger, Danville, PA, USA.
                [185 ]Department of Nephrology, Geisinger, Danville, PA, USA.
                [186 ]Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
                [187 ]Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
                [188 ]Cardiovascular Health Research Unit, Department of Medicine, Department of Epidemiology, Department of Health Service, University of Washington, Seattle, WA, USA.
                [189 ]Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
                [190 ]Department of Nephrology and Rheumatology, Kliniken Südostbayern AG, Regensburg, Germany.
                [191 ]Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
                [192 ]Laboratory for Statistical Analysis, RIKEN Centre for Integrative Medical Sciences (IMS), Osaka, Japan.
                [193 ]Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
                [194 ]Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Centre, Nashville, TN, USA.
                [195 ]Department of Veterans Affairs, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
                [196 ]These authors contributed equally to this work.
                [197 ]These authors jointly directed this project.
                Author notes

                Author contributions

                Manuscript writing group: Adrienne Tin, Jonathan Marten, Victoria L. Halperin Kuhns, Yong Li, Matthias Wuttke, Holger Kirsten, Karsten B. Sieber, Chengxiang Qiu, Mathias Gorski, Markus Scholz, Adriana M. Hung, Alexander Teumer, Cristian Pattaro, Owen M. Woodward, Veronique Vitart, Anna Köttgen

                Design of this study: Adrienne Tin, Jonathan Marten, Matthias Wuttke, Mathias Gorski, Christian Fuchsberger, Alexander Teumer, Cristian Pattaro, Owen M. Woodward, Veronique Vitart, Anna Köttgen

                Management of an individual contributing study: Adam S. Butterworth, Adriana M. Hung, Adrienne Tin, Afshin Parsa, Aiko P. J. de Vries, Alan B. Zonderman, Alessandro De Grandi, Andres Metspalu, Andrew A. Hicks, Anke Tönjes, Anna Köttgen, Annette Peters, Antje Körner, Antonietta Robino, Archie Campbell, Belen Ponte, Bernhard K. Krämer, Bettina Jung, Brenda W. J. H. Penninx, Bruce M. Psaty, Caroline Hayward, Carsten A. Böger, Cassandra N. Spracklen, Christian Gieger, Christopher J. O’Donnell, Cornelia M. van Duijn, Cristian Pattaro, Daniela Toniolo, Daniele Cusi, Deborah Mascalzoni, Eric Boerwinkle, Erik Ingelsson, Florian Kronenberg, Gardar Sveinbjornsson, Georg Ehret, Gerard Waeber, Ginevra Biino, Girish N. Nadkarni, Grant W. Montgomery, Harold Snieder, Helena Schmidt, Igor Rudan, J. Michael Gaziano, James F. Wilson, James G. Wilson, Jaspal S. Kooner, Jeffrey OConnell, Joachim Thiery, Johanne Tremblay, John B. Whitfield, John C. Chambers, Josef Coresh, Kai-Uwe Eckardt, Karen L. Mohlke, Kari Stefansson, Kevin Ho, Koichi Matsuda, Konstantin Strauch, M. Arfan Ikram, Marcus E. Kleber, Marina Ciullo, Mario Pirastu, Markus Loeffler, Markus Scholz, Martin H. de Borst, Matthias Wuttke, Michael Stumvoll, Michele K. Evans, Michiaki Kubo, Mika Kähönen, Murielle Bochud, Myriam Rheinberger, Nicholas G. Martin, Olivier Devuyst, Olli T. Raitakari, Ozren Polasek, Paolo Gasparini, Peter P. Pramstaller, Peter Vollenweider, Pim van der Harst, Qiong Yang, Rainer Rettig, Reinhold Schmidt, Renée de Mutsert, Robert J. Carroll, Ron T. Gansevoort, Ruth J. F. Loos, Sarah A. Pendergrass, Sarah H. Wild, Stephan J. L. Bakker, Tamara B. Harris, Terho Lehtimäki, Thomas Perls, Ton J. Rabelink, Uwe Völker, Vilmantas Giedraitis, Vilmundur Gudnason, Weihua Zhang, Wieland Kiess, Winfried März, Wolfgang Koenig, Yong Li, Yuri Milaneschi

                Critical review of manuscript: Adam S. Butterworth, Adriana M. Hung, Adrienne Tin, Afshin Parsa, Aiko P. J. de Vries, Alan B. Zonderman, Albert V. Smith, Alexander Teumer, André G. Uitterlinden, Anke Tönjes, Anna Köttgen, Annette Peters, Anselm Hoppmann, Antje Körner, Antonietta Robino, Anubha Mahajan, Audrey Y. Chu, Ayush Giri, Bernhard K. Krämer, Bettina Jung, Boting Ning, Bram Prins, Brenda W. J. H. Penninx, Brigitte Kühnel, Bruce M. Psaty, Caroline Hayward, Carsten A. Böger, Cassandra N. Spracklen, Chengxiang Qiu, Christa Meisinger, Christian Fuchsberger, Christian Gieger, Christopher J. O’Donnell, Cristian Pattaro, Daniel F. Gudbjartsson, Daniela Ruggiero, Deborah Mascalzoni, Dennis O. Mook-Kanamori, Erik Ingelsson, Erwin P. Bottinger, Eulalia Catamo, Florian Kronenberg, Gardar Sveinbjornsson, Ginevra Biino, Giorgia Girotto, Girish N. Nadkarni, Graciela Delgado, Grant W. Montgomery, Harold Snieder, Harry Campbell, Helgi Jonsson, Hilma Holm, Igor Rudan, Ilja M. Nolte, Ingileif Jonsdottir, Iris M. Heid, James F. Wilson, James G. Wilson, Johanna Jakobsdottir, Johanne Tremblay, John B. Whitfield, Jonathan Marten, Josef Coresh, Kai-Uwe Eckardt, Karen L. Mohlke, Karlhans Endlich, Karsten B. Sieber, Katalin Susztak, Kenneth M. Rice, Kevin Ho, Kjell Nikus, Konstantin Strauch, Laura M. Raffield, Leo-Pekka Lyytikäinen, Leslie A. Lange, Luke J. O’Connor, Man Li, Marcus E. Kleber, Marina Ciullo, Markus Loeffler, Markus Scholz, Martin H. de Borst, Martina La Bianca, Martina Müller-Nurasyid, Mary L. Biggs, Mathias Gorski, Matthias Nauck, Matthias Wuttke, Melanie Waldenberger, Michael H. Preuss, Michele K. Evans, Mika Kähönen, Mike A. Nalls, Myriam Rheinberger, Nicholas G. Martin, Niek Verweij, Nina Hutri-Kähöne, Nisha Bansal, Olivier Devuyst, Olli T. Raitakari, Otis D. Wilson, Ozren Polasek, Patrick Sulem, Pavel Hamet, Peter K. Joshi, Pim van der Harst, Qiong Yang, Rainer Rettig, Ravchel M. Lewis, Raymond Noordam, Renée de Mutsert, Ruth J. F. Loos, Sahar Ghasemi, Sala Cinzia Felicita, Salman M. Tajuddin, Sanaz Sedaghat, Sarah A. Pendergrass, Sarah H. Wild, Scott D. Gordon, Shih-Jen Hwang, Shona M. Kerr, Stephan J. L. Bakker, Tamara B. Harris, Teresa Nutile, Terho Lehtimäki, Thibaud S. Boutin, Thomas Meitinger, Todd L. Edwards, Ton J. Rabelink, Unnur Thorsteinsdottir, Uwe Völker, Veronique Vitart, Wei Huang, Winfried März, Wolfgang Koenig, Yong Li, Zhi Yu

                Statistical methods and analysis: Albert V. Smith, Alexander Teumer, Anna Köttgen, Anselm Hoppmann, Anubha Mahajan, Audrey Y. Chu, Ayse Demirkan, Ayush Giri, Bettina Jung, Boting Ning, Bram Prins, Brigitte Kühnel, Carsten A. Böger, Cassandra N. Spracklen, Chengxiang Qiu, Chris H. L. Thio, Christian Fuchsberger, Cristian Pattaro, Damia Noce, Daniel F. Gudbjartsson, Edith Hofer, Erika Salvi, Federica Rizzi, Gardar Sveinbjornsson, Ginevra Biino, Graciela Delgado, Holger Kirsten, Ilja M. Nolte, Iris M. Heid, Johanna Jakobsdottir, Johanne Tremblay, Jonathan Marten, Jun Liu, Karsten B. Sieber, Katalin Susztak, Kathleen A. Ryan, Katrin Horn, Kenneth M. Rice, Laura M. Raffield, Leo-Pekka Lyytikäinen, Leslie A. Lange, Man Li, Marco Brumat, Marcus E. Kleber, Maria Pina Concas, Markus Scholz, Martin Gögele, Mary L. Biggs, Masahiro Kanai, Masato Akiyama, Massimiliano Cocca, Mathias Gorski, Matthias Nauck, Matthias Wuttke, Michael H. Preuss, Mike A. Nalls, Myriam Rheinberger, Navya Shilpa Josyula, Nicola Pirastu, Niek Verweij, Nina Mononen, Pashupati P. Mishra, Pavel Hamet, Peter J. van der Most, Peter K. Joshi, Pim van der Harst, Qiong Yang, Raymond Noordam, Rico Rueedi, Robert J. Carroll, Sahar Ghasemi, Salman M. Tajuddin, Sanaz Sedaghat, Sarah A. Pendergrass, Shih-Jen Hwang, Tanguy Corre, Teresa Nutile, Thibaud S. Boutin, Todd L. Edwards, Toomas Haller, Veronique Vitart, Weihua Zhang, Winfried März, Yasaman Saba, Yizhe Xu, Yoichiro Kamatani, Yong Li, Yukinori Okada

                Subject recruitment: Aiko P. J. de Vries, Alan B. Zonderman, Andrej Teren, Andres Metspalu, Anke Tönjes, Anna Köttgen, Archie Campbell, Belen Ponte, Bettina Jung, Blair H. Smith, Brenda W. J. H. Penninx, Carsten A. Böger, Christa Meisinger, Cristian Pattaro, Daniela Ruggiero, Daniele Cusi, David J. Porteous, Erwin P. Bottinger, Florian Kronenberg, Gerard Waeber, Harry Campbell, Helgi Jonsson, Igor Rudan, Isleifur Olafsson, James F. Wilson, James G. Wilson, Jaspal S. Kooner, Johan Ärnlöv, Johanne Tremblay, John B. Whitfield, John C. Chambers, Katalin Dittrich, Kjell Nikus, Koichi Matsuda, Marina Ciullo, Michele K. Evans, Michiaki Kubo, Mika Kähönen, Myriam Rheinberger, Nicholas G. Martin, Nina Hutri-Kähöne, Olli T. Raitakari, Ozren Polasek, Patrick Sulem, Peter Vollenweider, Reinhold Schmidt, Renée de Mutsert, Ron T. Gansevoort, Saima Afaq, Sandosh Padmanabhan, Sarah A. Pendergrass, Sarah H. Wild, Simona Vaccargiu, Tanja Poulain, Terho Lehtimäki, Ton J. Rabelink, Vilmundur Gudnason, Wei Huang, Winfried März

                Bioinformatics: Albert V. Smith, Anna Köttgen, Anselm Hoppmann, Audrey Y. Chu, Ayush Giri, Benjamin Lehne, Bram Prins, Carsten A. Böger, Cassandra N. Spracklen, Chengxiang Qiu, Christian M. Shaffer, Daniela Baptista, Dennis O. Mook-Kanamori, Edith Hofer, Eric Campana, Erika Salvi, Federica Rizzi, Georg Ehret, Giorgio Pistis, Holger Kirsten, Iris M. Heid, James F. Wilson, Johanna Jakobsdottir, Johanne Tremblay, Jonathan Marten, Karen L. Mohlke, Karsten B. Sieber, Katalin Susztak, Katrin Horn, Leo-Pekka Lyytikäinen, Man Li, Marcus E. Kleber, Maria Pina Concas, Markus Scholz, Massimiliano Cocca, Mathias Gorski, Matthias Wuttke, Michael H. Preuss, Navya Shilpa Josyula, Nicola Pirastu, Pashupati P. Mishra, Pavel Hamet, Peter J. van der Most, Raymond Noordam, Reedik Magi, Rico Rueedi, Robert J. Carroll, Sahar Ghasemi, Sanaz Sedaghat, Sarah A. Pendergrass, Scott D. Gordon, Sven Bergmann, Tanguy Corre, Teresa Nutile, Weihua Zhang, Winfried März, Yasaman Saba, Yizhe Xu, Yong Li, Yuri Milaneschi, Zhi Yu

                Interpretation of results: Adrienne Tin, Alexander Teumer, André G. Uitterlinden, Anna Köttgen, Ayush Giri, Bettina Jung, Carsten A. Böger, Cassandra N. Spracklen, Chengxiang Qiu, Christian Gieger, Christopher J. O’Donnell, Cristian Pattaro, Helgi Jonsson, Holger Kirsten, Iris M. Heid, Johanne Tremblay, Jonathan Marten, Karen L. Mohlke, Karlhans Endlich, Karsten B. Sieber, Katalin Dittrich, Katalin Susztak, Katrin Horn, Kevin Ho, Luke J. O’Connor, Man Li, Markus Scholz, Mathias Gorski, Matthias Wuttke, Myriam Rheinberger, Niek Verweij, Owen M. Woodward, Pavel Hamet, Pim van der Harst, Sahar Ghasemi, Sanaz Sedaghat, Sarah A. Pendergrass, Shih-Jen Hwang, Veronique Vitart, Victoria L. Halperin Kuhns, Wei Huang, Wolfgang Koenig, Yizhe Xu, Yong Li

                Genotyping: Alan B. Zonderman, Alexander Teumer, André G. Uitterlinden, Antje Körner, Archie Campbell, Ayse Demirkan, Blair H. Smith, Brenda W. J. H. Penninx, Caroline Hayward, Carsten A. Böger, Cassandra N. Spracklen, Christian Fuchsberger, Cornelia M. van Duijn, Daniela Baptista, Daniela Ruggiero, Daniela Toniolo, David J. Porteous, Dennis O. Mook-Kanamori, Erik Ingelsson, Erika Salvi, Federica Rizzi, Florian Kronenberg, Georg Ehret, Grant W. Montgomery, Harry Campbell, James F. Wilson, James G. Wilson, Jaspal S. Kooner, Johan Ärnlöv, Johanne Tremblay, John C. Chambers, Karen L. Mohlke, Leo-Pekka Lyytikäinen, Leslie A. Lange, Marcus E. Kleber, Melanie Waldenberger, Michael H. Preuss, Michele K. Evans, Michiaki Kubo, Mika Kähönen, Mike A. Nalls, Najaf Amin, Nina Mononen, Olli T. Raitakari, Patrick Sulem, Pavel Hamet, Peter Kovacs, Pim van der Harst, Ralph Burkhardt, Ron T. Gansevoort, Salman M. Tajuddin, Sandosh Padmanabhan, Scott D. Gordon, Simona Vaccargiu, Terho Lehtimäki, Thomas Meitinger, Uwe Völker, Wei Huang, Winfried März, Wolfgang Koenig, Yuri Milaneschi

                Functional study: Victoria Halperin Kuhns, Raychel Lewis, Owen M. Woodward

                Article
                NIHMS1538428
                10.1038/s41588-019-0504-x
                6858555
                31578528
                caa8f8db-623d-41e1-bdc5-f65f3e5fa897

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