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Abstract
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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1 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
2 Institute of Genetic Epidemiology, Department of Biometry, Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
3 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
4 Institute of Genetic Epidemiology, Department of Biometry, Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany; Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
5 Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
6 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; Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA
7 Target Sciences - Genetics, GlaxoSmithKline, Collegeville, PA, USA
8 Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA
9 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany
10 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Epidemiology and Clinical Research, Welch Centre for Prevention, Baltimore, MD, USA
11 Genetics, Merck & Co., Inc., Kenilworth, NJ, USA
12 Division of Nephrology, University of Washington, Seattle, WA, USA; Kidney Research Institute, University of Washington, Seattle, WA, USA
13 Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
14 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
15 Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, Trieste, Italy
16 Eurac Research, Institute for Biomedicine (affiliated to the University of Lübeck), Bolzano, Italy
17 Department of Nephrology, University Hospital Regensburg, Regensburg, Germany; Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
18 Department of Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA
19 Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
20 Institute of Genetics and Biophysics “Adriano Buzzati-Traverso” - CNR, Naples, Italy
21 Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
22 deCODE Genetics, Amgen Inc., Reykjavik, Iceland
23 Department of Public Health Sciences, Loyola University Chicago, Maywood, IL, USA
24 Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
25 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
26 Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden
27 Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
28 Cardiology, Geneva University Hospitals, Geneva, Switzerland
29 Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA
30 Human Genetics Centre, University of Texas Health Science Centre, Houston, TX, USA
31 Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Heidelberg, Germany; Network Aging Research, University of Heidelberg, Heidelberg, Germany
32 LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany
33 Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
34 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
35 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore
36 Department of Biostatistics, University of Liverpool, Liverpool, UK
37 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
38 Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
39 Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK
40 Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
41 Section of Nephrology, Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands
42 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
43 Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany; Centre for Pediatric Research, University of Leipzig, Leipzig, Germany
44 Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA
45 Intensive Care Medicine, Charité, Berlin, Germany; Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
46 DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany; Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
47 Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
48 Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
49 Internal Medicine - Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA
50 Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, Kiel, USA
51 Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala, Sweden
52 Icelandic Heart Association, Kopavogur, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
53 Montreal University Hospital Research Centre, CHUM, Montreal, QC, Canada; Medpharmgene, Montreal, QC, Canada
54 Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA
55 NHLBI’s Framingham Heart Study, Framingham, MA, USA; The Centre for Population Studies, NHLBI, Framingham, MA, USA
56 Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
57 Icelandic Heart Association, Holtasmari 1, Kopavogur, Iceland; The Centre of Public Health Sciences, University of Iceland, Sturlugata 8, Reykjavík, Iceland
58 Geisinger Research, Biomedical and Translational Informatics Institute, Rockville, MD, USA
59 Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
60 Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland; Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
61 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore; Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore
62 LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany; Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany; Centre for Pediatric Research, University of Leipzig, Leipzig, Germany
63 Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology and Biostatistics, University of Ulm, Ulm, Germany
64 Integrated Research and Treatment Centre Adiposity Diseases, University of Leipzig, Leipzig, Germany
65 Department of Public Health Sciences, Loyola University Chicago, Maywood, IL, USA; Division of Nephrology and Hypertension, Loyola University Chicago, Chicago, IL, USA
66 5th Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
67 Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
68 Division of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, USA
69 Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
70 Institute of Epidemiology and Biobank Popgen, Kiel University, Kiel, Germany
71 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore; Diabetes Centre, Khoo Teck Puat Hospital, Singapore, Singapore
72 Cardiovascular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
73 Nuffield Department of Medicine, University of Oxford, Oxford, UK; Broad Institute of Harvard and MIT, Cambridge, MA, USA
74 Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore
75 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
76 MRL, Merck & Co., Inc., Kenilworth, NJ, USA; Celgene Inc., Cambridge, MA, USA
77 Vanderbilt University School of Medicine, Nashville, TN, USA
78 Independent Research Group Clinical Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; Chair of Epidemiology Ludwig- Maximilians-Universität München at UNIKA-T Augsburg, Augsburg, Germany
79 DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany
80 Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands; Department of Public Health and Primary Care, Leiden University Medical Centre, Leiden, The Netherlands
81 Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany; Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU, Munich, Germany; Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
82 Centre for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
83 DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
84 Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, Finland; Department of Cardiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
85 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
86 Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands
87 University of Maryland School of Medicine, Baltimore, MD, USA
88 Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, Iceland
89 Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
90 DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
91 Service de Néphrologie, Geneva University Hospitals, Geneva, Switzerland
92 LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany
93 Section of Nephrology, Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands; Einthoven Laboratory of Experimental Vascular Research, Leiden University Medical Centre, Leiden, The Netherlands
94 Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
95 Institute of Physiology, University Medicine Greifswald, Karlsburg, Germany
96 Department of Biostatistics, University of Washington, Seattle, WA, USA
97 Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
98 MRL, Merck & Co., Inc., Kenilworth, NJ, USA; Biogen Inc., Cambridge, MA, USA
99 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
100 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore
101 Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Heidelberg, Germany
102 Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
103 Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany; Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU, Munich, Germany
104 Department of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany
105 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore
106 The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
107 LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany; Heart Centre Leipzig, Leipzig, Germany
108 LIFE Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany
109 Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
110 Montreal University Hospital Research Centre, CHUM, Montreal, QC, Canada; CRCHUM, Montreal, QC, Canada
111 Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
112 Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Durrer Centre for Cardiovascular Research, The Netherlands Heart Institute, Utrecht, The Netherlands
113 Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
114 DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
115 DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany
116 Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore; School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
117 Vanderbilt University Medical Centre, Division of Nephrology & Hypertension, Nashville, TN, USA
118 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore
119 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore; Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan
120 Kidney Research Institute, University of Washington, Seattle, WA, USA; Anatomic Pathology, University of Washington Medical Center, Seattle, WA, USA
121 Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
122 Department of Nephrology, University Hospital Regensburg, Regensburg, Germany; Department of Nephrology, Diabetology and Rheumatology, Kliniken Südostbayern, Traunstein, Germany
123 Institute of Physiology, University of Zurich, Zurich, Switzerland
124 Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Centre, Nashville, TN, USA; Department of Veteran’s Affairs, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA
125 Kidney Health Research Institute (KHRI), Geisinger, Danville, PA, USA; Department of Nephrology, Geisinger, Danville, PA, USA
126 Department of Biostatistics, University of Liverpool, Liverpool, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
127 Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
128 Geisinger Research, Biomedical and Translational Informatics Institute, Danville, PA, USA
129 Cardiovascular Health Research Unit, Department of Medicine, Department of Epidemiology, Department of Health Service, University of Washington, Seattle, WA, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
130 The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA; Department of Pediatrics, Harbor-UCLA Medical Centre, Torrance, CA, USA; Department of Medicine, Harbor-UCLA Medical Centre, Torrance, CA, USA
131 Department of Physiology and Biophysics, University of Mississippi Medical Centre, Jackson, MS, USA
132 Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
133 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK
134 Vanderbilt University Medical Centre, Division of Nephrology & Hypertension, Nashville, TN, USA; Department of Veteran’s Affairs, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA
135 Institute of Genetic Epidemiology, Department of Biometry, Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA