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Nat Genet. 2019 Oct 2. doi: 10.1038/s41588-019-0504-x. [Epub ahead of print]

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

Tin A1,2, Marten J3, Halperin Kuhns VL4, Li Y5, Wuttke M5, Kirsten H6,7, Sieber KB8, Qiu C9, Gorski M10,11, Yu Z12,13, Giri A14,15, Sveinbjornsson G16, Li M17, Chu AY18, Hoppmann A5, O'Connor LJ19, Prins B20, Nutile T21, Noce D22, Akiyama M23,24, Cocca M25, Ghasemi S26,27, van der Most PJ28, Horn K6,7, Xu Y17, Fuchsberger C22, Sedaghat S29, Afaq S30,31, Amin N29, Ärnlöv J32,33, Bakker SJL34, Bansal N35,36, Baptista D37, Bergmann S38,39,40, Biggs ML41,42, Biino G43, Boerwinkle E44, Bottinger EP45, Boutin TS3, Brumat M46, Burkhardt R7,47,48, Campana E46, Campbell A49, Campbell H50, Carroll RJ51, Catamo E25, Chambers JC30,52,53,54,55, Ciullo M21,56, Concas MP25, Coresh J12, Corre T38,39,57, Cusi D58,59, Felicita SC60, de Borst MH34, De Grandi A22, de Mutsert R61, de Vries APJ62, Delgado G63, Demirkan A29,64, Devuyst O65, Dittrich K66,67, Eckardt KU68,69, Ehret G37, Endlich K27,70, Evans MK71, Gansevoort RT34, Gasparini P25,46, Giedraitis V72, Gieger C73,74,75, Girotto G25,46, Gögele M22, Gordon SD76, Gudbjartsson DF16, Gudnason V77,78; German Chronic Kidney Disease Study, Haller T79, Hamet P80,81, Harris TB82, Hayward C3, Hicks AA22, Hofer E83,84, Holm H16, Huang W85,86, Hutri-Kähönen N87,88, Hwang SJ89,90, Ikram MA29, Lewis RM4, Ingelsson E91,92,93,94, Jakobsdottir J77,95, Jonsdottir I16, Jonsson H96,97, Joshi PK50, Josyula NS98, Jung B10, Kähönen M99, Kamatani Y23,100, Kanai M23,101, Kerr SM3, Kiess W7,66,67, Kleber ME63, Koenig W102,103,104, Kooner JS53,54,105,106, Körner A7,66,67, Kovacs P107, Krämer BK63, Kronenberg F108, Kubo M109, Kühnel B73, La Bianca M25, Lange LA110, Lehne B30, Lehtimäki T87; Lifelines Cohort Study, Liu J29,111, Loeffler M6,7, Loos RJF112,113, Lyytikäinen LP87, Magi R79, Mahajan A114,115, Martin NG76, März W63,116,117, Mascalzoni D22, Matsuda K118, Meisinger C119,120, Meitinger T103,121,122, Metspalu A79, Milaneschi Y123; V. A. Million Veteran Program, O'Donnell CJ124,125, Wilson OD126, Gaziano JM125,127, Mishra PP87, Mohlke KL128, Mononen N87, Montgomery GW129, Mook-Kanamori DO61,130, Müller-Nurasyid M103,131,132,133, Nadkarni GN112,134, Nalls MA135,136, Nauck M27,137, Nikus K138,139, Ning B140, Nolte IM28, Noordam R141, O'Connell JR142, Olafsson I143, Padmanabhan S144, Penninx BWJH123, Perls T145, Peters A74,75,103, Pirastu M146, Pirastu N50, Pistis G147, Polasek O148,149, Ponte B150, Porteous DJ49,151, Poulain T7, Preuss MH112, Rabelink TJ62,152, Raffield LM128, Raitakari OT153,154,155, Rettig R156, Rheinberger M10, Rice KM42, Rizzi F157,158, Robino A25, Rudan I50, Krajcoviechova A159,160, Cifkova R159,161, Rueedi R38,39, Ruggiero D21,56, Ryan KA162, Saba Y163, Salvi E157,164, Schmidt H165, Schmidt R83, Shaffer CM51, Smith AV78, Smith BH166, Spracklen CN128, Strauch K131,132, Stumvoll M167, Sulem P16, Tajuddin SM71, Teren A7,168, Thiery J7,47, Thio CHL28, Thorsteinsdottir U16, Toniolo D60, Tönjes A169, Tremblay J80,170, Uitterlinden AG171, Vaccargiu S146, van der Harst P172,173,174, van Duijn CM29,111,175, Verweij N172,176, Völker U27,177, Vollenweider P178, Waeber G178, Waldenberger M73,74,103, Whitfield JB76, Wild SH179, Wilson JF3,50, Yang Q140, Zhang W30,53, Zonderman AB71, Bochud M57, Wilson JG180, Pendergrass SA181, Ho K182,183, Parsa A184,185, Pramstaller PP22, Psaty BM186,187, Böger CA10,188, Snieder H28, Butterworth AS189, Okada Y190,191, Edwards TL192,193, Stefansson K16, Susztak K9, Scholz M6,7, Heid IM11, Hung AM126,193, Teumer A26,27, Pattaro C22, Woodward OM4, Vitart V3, Köttgen A194,195.

Author information

1
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. atin1@jhu.edu.
2
Welch Centre for Prevention, Epidemiology and Clinical Research, Baltimore, MD, USA. atin1@jhu.edu.
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
Department of Medicine and Genetics, 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 Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
13
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
14
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.
15
Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
16
deCODE Genetics, Amgen Inc., Reykjavik, Iceland.
17
Department of Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA.
18
Genetics, Merck & Co., Inc, Kenilworth, NJ, USA.
19
Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
20
Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.
21
Institute of Genetics and Biophysics Adriano Buzzati-Traverso-CNR, Naples, Italy.
22
Eurac Research, Institute for Biomedicine, Bolzano, Italy.
23
Laboratory for Statistical Analysis, RIKEN Centre for Integrative Medical Sciences, Yokohama (Kanagawa), Japan.
24
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
25
Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy.
26
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
27
DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany.
28
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
29
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
30
Department of Epidemiology and Biostatistics, Faculty of Medicine, School of Public Health, Imperial College London, London, UK.
31
Institute of Public Health & Social Sciences, Khyber Medical University, Peshawar, Pakistan.
32
Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.
33
School of Health and Social Studies, Dalarna University, Falun, Sweden.
34
Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
35
Division of Nephrology, University of Washington, Seattle, WA, USA.
36
Kidney Research Institute, University of Washington, Seattle, WA, USA.
37
Cardiology, Geneva University Hospitals, Geneva, Switzerland.
38
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
39
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
40
Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
41
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
42
Department of Biostatistics, University of Washington, Seattle, WA, USA.
43
Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy.
44
Human Genetics Centre, University of Texas Health Science Centre, Houston, TX, USA.
45
Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
46
University of Trieste, Department of Medicine, Surgery and Health Sciences, Trieste, Italy.
47
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany.
48
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany.
49
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
50
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
51
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
52
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
53
Department of Cardiology, Ealing Hospital, London, UK.
54
Imperial College Healthcare NHS Trust, Imperial College London, London, UK.
55
MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
56
IRCCS Neuromed, Pozzilli, Italy.
57
Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland.
58
Institute of Biomedical Technologies, Italy National Research Council, Milano, Italy.
59
Bio4Dreams, Milano, Italy.
60
San Raffaele Research Institute, Milano, Italy.
61
Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands.
62
Section of Nephrology, Department of Internal Medicine, Leiden University Medical Centre, Leiden, the Netherlands.
63
Fifth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
64
Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
65
Institute of Physiology, University of Zurich, Zurich, Switzerland.
66
Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
67
Centre for Pediatric Research, University of Leipzig, Leipzig, Germany.
68
Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
69
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
70
Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
71
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
72
Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala, Sweden.
73
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Centre for Environmental Health, Neuherberg, Germany.
74
Institute of Epidemiology, Helmholtz Zentrum München-German Research Centre for Environmental Health, Neuherberg, Germany.
75
German Center for Diabetes Research, Neuherberg, Germany.
76
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
77
Icelandic Heart Association, Kópavogur, Iceland.
78
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
79
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
80
Montreal University Hospital Research Centre, Centre Hospitalier de lUniversité de Montréal, Montreal, Quebec, Canada.
81
Medpharmgene, Montreal, Quebec, 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
National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, USA.
90
The Centre for Population Studies, National Heart, Lung, and Blood Institute, Framingham, MA, USA.
91
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
92
Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
93
Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
94
Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
95
The Centre of Public Health Sciences, University of Iceland, Reykjavik, Iceland.
96
Landspitalinn University Hospital, Reykjavík, Iceland.
97
University of Iceland, Reykjavík, Iceland.
98
Geisinger Research, Biomedical and Translational Informatics Institute, Rockville, MD, USA.
99
Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
100
Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
101
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
102
Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
103
German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany.
104
Institute of Epidemiology and Biostatistics, University of Ulm, Ulm, Germany.
105
MRC-PHE Centre for Environment and Health, 323 School of Public Health, Imperial College London, London, UK.
106
National Heart and Lung Institute, Imperial College London, London, UK.
107
Integrated Research and Treatment Centre Adiposity Diseases, University of Leipzig, Leipzig, Germany.
108
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
109
RIKEN Centre for Integrative Medical Sciences, Yokohama (Kanagawa), Japan.
110
Division of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO, USA.
111
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
112
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
113
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
114
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
115
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
116
Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
117
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
118
Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
119
Independent Research Group Clinical Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
120
Ludwig-Maximilians-Universität München at UNIKA-T Augsburg, Augsburg, Germany.
121
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
122
Institute of Human Genetics, Technische Universität München, Munich, Germany.
123
Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
124
VA Boston Healthcare System, Boston, MA, USA.
125
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
126
Vanderbilt University Medical Centre, Division of Nephrology & Hypertension, Nashville, TN, USA.
127
Massachusetts Veterans Epidemiology Research and Information Center, VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.
128
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
129
University of Queensland, St Lucia, Queensland, Australia.
130
Department of Public Health and Primary Care, Leiden University Medical Centre, Leiden, the Netherlands.
131
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Centre for Environmental Health, Neuherberg, Germany.
132
Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
133
Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany.
134
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
135
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
136
Data Tecnica International, Glen Echo, MD, USA.
137
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
138
Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, Finland.
139
Department of Cardiology, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
140
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
141
Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Centre, Leiden, the Netherlands.
142
University of Maryland School of Medicine, Baltimore, MD, USA.
143
Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, Iceland.
144
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
145
Department of Medicine, Geriatrics Section, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.
146
Institute of Genetic and Biomedical Research, National Research Council of Italy, UOS of Sassari, Sassari, Italy.
147
Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
148
Faculty of Medicine, University of Split, Split, Croatia.
149
Gen-info Ltd, Zagreb, Croatia.
150
Nephrology Service, Department of Specialties in Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland.
151
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
152
Einthoven Laboratory of Experimental Vascular Research, Leiden University Medical Centre, Leiden, the Netherlands.
153
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
154
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
155
Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
156
Institute of Physiology, University Medicine Greifswald, Karlsburg, Germany.
157
Department of Health Sciences, University of Milan, Milano, Italy.
158
ePhood Scientific Unit, ePhood SRL, Milano, Italy.
159
Center for Cardiovascular Prevention, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic.
160
Thomayer Hospital, Prague, Czech Republic.
161
Department of Medicine II, First Faculty of Medicine, Charles University, Prague, Czech Republic.
162
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
163
Molecular Biology and Biochemistry, Gottfried Schatz Research Centre for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria.
164
Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
165
Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria.
166
Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
167
Division of Endocrinology, Nephrology and Rheumatology, University of Leipzig, Leipzig, Germany.
168
Heart Centre Leipzig, Leipzig, Germany.
169
Department of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
170
Centre de Recherche du CHUM, Montreal, Quebec, Canada.
171
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
172
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
173
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
174
Durrer Centre for Cardiovascular Research, the Netherlands Heart Institute, Utrecht, the Netherlands.
175
Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
176
Genomics plc, Oxford, UK.
177
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
178
Internal Medicine, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
179
Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
180
Department of Physiology and Biophysics, University of Mississippi Medical Centre, Jackson, MS, USA.
181
Geisinger Research, Biomedical and Translational Informatics Institute, Danville, PA, USA.
182
Kidney Health Research Institute, Geisinger, Danville, PA, USA.
183
Department of Nephrology, Geisinger, Danville, PA, USA.
184
Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
185
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
186
Cardiovascular Health Research Unit, Department of Medicine, Department of Epidemiology, Department of Health Service, University of Washington, Seattle, WA, USA.
187
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
188
Department of Nephrology and Rheumatology, Kliniken Südostbayern AG, Traunstein, Germany.
189
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
190
Laboratory for Statistical Analysis, RIKEN Centre for Integrative Medical Sciences, Osaka, Japan.
191
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
192
Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Centre, Nashville, TN, USA.
193
Department of Veterans Affairs, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
194
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. anna.koettgen@uniklinik-freiburg.de.
195
Institute of Genetic Epidemiology, Department of Biometry, Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany. anna.koettgen@uniklinik-freiburg.de.

Abstract

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

PMID:
31578528
DOI:
10.1038/s41588-019-0504-x

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