5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

      , 1 , 2 , 3 , 4 , 5 , 3 , 5 , 6 , 3 , 7 , 8 , 6 , 8 , 9 , 10 , 11 , 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 15 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 24 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 40 , 40 , 10 , 44 , 45 , 10 , 26 , 46 , 47 , 48 , 40 , 49 , 50 , 16 , 51 , 4 , 1 , 2 , 52 , 6 , 53 , 54 , 55 , 34 , 56 , 57 , 11 , 58 , 1 , 59 , 60 , 41 , 61 , 62 , 63 , 64 , 45 , 60 , 65 , 26 , 27 , Lifelines Cohort Study, 16 , 20 , 23 , 66 , 22 , 40 , 67 , 68 , 42 , 69 , 49 , 70 , 71 , 68 , 15 , 72 , 73 , 11 , 74 , 75 , 24 , 40 , 10 , 76 , 24 , 77 , 78 , 40 , 79 , 80 , 49 , 42 , 27 , 81 , 82 , 83 , 84 , 4 , 5 , 60 , 85 , 8 , 86 , 87 , 15 , 88 , 10 , 89 , 82 , 26 , 90 , 91 , 92 , 40 , 35 , 23 , 69 , 8 , 4 , 5 , 3 , 5 , 20 , 51 , 20 , 51 , 82 , 93 , 65 , 94 , 95 , 96 , 3 , 5 , 24 , 1 , 2 , 24 , 97 , 6 , 98 , 3 , 5 , 3 , 4 , 5

      Nature Communications

      Nature Publishing Group UK

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

          Abstract

          Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.

          Related collections

          Most cited references 42

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

          The clinical significance of subclinical thyroid dysfunction.

          Subclinical thyroid disease (SCTD) is defined as serum free T(4) and free T(3) levels within their respective reference ranges in the presence of abnormal serum TSH levels. SCTD is being diagnosed more frequently in clinical practice in young and middle-aged people as well as in the elderly. However, the clinical significance of subclinical thyroid dysfunction is much debated. Subclinical hyper- and hypothyroidism can have repercussions on the cardiovascular system and bone, as well as on other organs and systems. However, the treatment and management of SCTD and population screening are controversial despite the potential risk of progression to overt disease, and there is no consensus on the thyroid hormone and thyrotropin cutoff values at which treatment should be contemplated. Opinions differ regarding tissue effects, symptoms, signs, and cardiovascular risk. Here, we critically review the data on the prevalence and progression of SCTD, its tissue effects, and its prognostic implications. We also examine the mechanisms underlying tissue alterations in SCTD and the effects of replacement therapy on progression and tissue parameters. Lastly, we address the issue of the need to treat slight thyroid hormone deficiency or excess in relation to the patient's age.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping.

             Steve Brown,  R. Moore (2012)
            Determining the function of all mammalian genes remains a major challenge for the biomedical science community in the 21st century. The goal of the International Mouse Phenotyping Consortium (IMPC) over the next 10 years is to undertake broad-based phenotyping of 20,000 mouse genes, providing an unprecedented insight into mammalian gene function. This short article explores the drivers for large-scale mouse phenotyping and provides an overview of the aims and processes involved in IMPC mouse production and phenotyping.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter.

              Transport of thyroid hormone across the cell membrane is required for its action and metabolism. Recently, a T-type amino acid transporter was cloned which transports aromatic amino acids but not iodothyronines. This transporter belongs to the monocarboxylate transporter (MCT) family and is most homologous with MCT8 (SLC16A2). Therefore, we cloned rat MCT8 and tested it for thyroid hormone transport in Xenopus laevis oocytes. Oocytes were injected with rat MCT8 cRNA, and after 3 days immunofluorescence microscopy demonstrated expression of the protein at the plasma membrane. MCT8 cRNA induced an approximately 10-fold increase in uptake of 10 nM 125I-labeled thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3) and 3,3'-diiodothyronine. Because of the rapid uptake of the ligands, transport was only linear with time for <4 min. MCT8 did not transport Leu, Phe, Trp, or Tyr. [125I]T4 transport was strongly inhibited by L-T4, D-T4, L-T3, D-T3, 3,3',5-triiodothyroacetic acid, N-bromoacetyl-T3, and bromosulfophthalein. T3 transport was less affected by these inhibitors. Iodothyronine uptake in uninjected oocytes was reduced by albumin, but the stimulation induced by MCT8 was markedly increased. Saturation analysis provided apparent Km values of 2-5 microM for T4, T3, and rT3. Immunohistochemistry showed high expression in liver, kidney, brain, and heart. In conclusion, we have identified MCT8 as a very active and specific thyroid hormone transporter.
                Bookmark

                Author and article information

                Contributors
                ateumer@uni-greifswald.de
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                26 October 2018
                26 October 2018
                2018
                : 9
                Affiliations
                [1 ]GRID grid.5603.0, Institute for Community Medicine, , University Medicine Greifswald, ; Greifswald, Germany
                [2 ]DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
                [3 ]ISNI 000000040459992X, GRID grid.5645.2, Erasmus MC Academic Center for Thyroid Diseases, ; Rotterdam, The Netherlands
                [4 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Epidemiology, , Erasmus Medical Center, ; Rotterdam, The Netherlands
                [5 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Internal Medicine, , Erasmus Medical Center, ; Rotterdam, The Netherlands
                [6 ]ISNI 0000 0000 9428 7911, GRID grid.7708.8, Department of Biometry, Epidemiology and Medical Bioinformatics, Institute of Genetic Epidemiology, , Faculty of Medicine and Medical Center—University of Freiburg, ; Freiburg, Germany
                [7 ]ISNI 0000 0001 0724 3038, GRID grid.47422.37, Department of Science and Technologies, , University of Sannio, ; Benevento, Italy
                [8 ]ISNI 0000000417581884, GRID grid.18887.3e, Division of Genetics and Cell Biology, , San Raffaele Scientific Institute, ; Milan, Italy
                [9 ]ISNI 0000 0004 0646 7285, GRID grid.419658.7, Steno Diabetes Center Copenhagen, ; Gentofte, Denmark
                [10 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, ; Copenhagen, Denmark
                [11 ]Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
                [12 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, ; Baltimore, MD USA
                [13 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Biostatistics, , University of Washington, ; Seattle, WA USA
                [14 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Department of Nutrition, Exercise, and Sports, Faculty of Science, , University of Copenhagen, ; Copenhagen, Denmark
                [15 ]ISNI 0000000089452978, GRID grid.10419.3d, Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, ; Leiden, The Netherlands
                [16 ]ISNI 0000 0004 0589 6117, GRID grid.2824.c, Pathwest Laboratory Medicine WA, ; Nedlands, WA 6009 Australia
                [17 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, School of Biomedical Sciences, , University of Western Australia, ; Crawley, WA 6009 Australia
                [18 ]ISNI 0000 0004 0626 3303, GRID grid.410566.0, Bimetra, Clinical Research Center Ghent, , Ghent University Hospital, ; Ghent, Belgium
                [19 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Human Genetics Center, , University of Texas Health Science Center, ; 1200 Pressler Street, Houston, TX 77030 USA
                [20 ]ISNI 0000 0004 0437 5942, GRID grid.3521.5, Department of Endocrinology and Diabetes, , Sir Charles Gairdner Hospital, ; Nedlands, WA 6009 Australia
                [21 ]ISNI 0000 0004 0626 3303, GRID grid.410566.0, Department of Cardiology, , Ghent University Hospital, ; Ghent, Belgium
                [22 ]Department of Medicine and Surgery, University of Parma, University Hospital of Parma, Parma, Italy
                [23 ]Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark
                [24 ]ISNI 0000 0004 1789 9390, GRID grid.428485.7, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, ; Monserrato, Italy
                [25 ]ISNI 0000 0001 2097 9138, GRID grid.11450.31, Dipartimento di Scienze Biomediche, , Università degli Studi di Sassari, ; Sassari, Italy
                [26 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Centre for Cognitive Ageing and Cognitive Epidemiology, , University of Edinburgh, ; Edinburgh, UK
                [27 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Department of Psychology, , University of Edinburgh, ; Edinburgh, UK
                [28 ]ISNI 0000 0004 0373 6590, GRID grid.419502.b, Max Planck Institute for Biology of Ageing, ; Cologne, Germany
                [29 ]ISNI 0000 0001 2107 3311, GRID grid.5330.5, Department of Nephrology and Hypertension, , University of Erlangen-Nürnberg, ; Erlangen, Germany
                [30 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Department of Nephrology and Medical Intensive Care, , Charité – Universitätsmedizin Berlin, ; Berlin, Germany
                [31 ]ISNI 0000 0001 2107 3311, GRID grid.5330.5, Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), ; Erlangen, Germany
                [32 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of General Practice and Primary Health Care, , University of Helsinki and Helsinki University Hospital, ; Helsinki, Finland
                [33 ]ISNI 0000 0004 0409 6302, GRID grid.428673.c, Folkhälsan Research Center, ; Helsinki, Finland
                [34 ]ISNI 0000 0001 1013 0499, GRID grid.14758.3f, National Institute for Health and Welfare, ; Helsinki, Finland
                [35 ]ISNI 0000 0000 9372 4913, GRID grid.419475.a, Translational Gerontology Branch, , National Institute on Aging, ; Baltimore, MD USA
                [36 ]ISNI 0000 0004 0626 3303, GRID grid.410566.0, Department of Clinical Chemistry, , Ghent University Hospital, ; Ghent, Belgium
                [37 ]ISNI 0000 0001 2193 314X, GRID grid.8756.c, Robertson Centre for Biostatistics, , University of Glasgow, ; Glasgow, UK
                [38 ]ISNI 0000 0001 2293 4638, GRID grid.279885.9, National Heart, Lung, and Blood Institute’s Framingham Heart Study and the Center for Population Studies, ; Framingham, MA USA
                [39 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Division of Endocrinology, , Brigham and Women’s Hospital and Harvard Medical School, ; Boston, MA USA
                [40 ]Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy
                [41 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Radboud University Medical Center, , Radboud Institute for Health Sciences, ; Nijmegen, The Netherlands
                [42 ]ISNI 0000 0004 0483 2525, GRID grid.4567.0, Helmholtz Zentrum München, Institute of Epidemiology, , German Research Center for Environmental Health, ; Neuherberg, Germany
                [43 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany
                [44 ]German Research Centre Division of Cancer Epidemiology, Heidelberg, Germany
                [45 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of Psychology and Logopedics, Faculty of Medicine, , University of Helsinki, ; Helsinki, Finland
                [46 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Medical Genetics Section, , University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, ; Edinburgh, UK
                [47 ]ISNI 0000000089452978, GRID grid.10419.3d, Leiden University Medical Center, Geriatrics and Gerontology, ; Leiden, The Netherlands
                [48 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Vrije Universiteit Medisch Centrum, ; Amsterdam, The Netherlands
                [49 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Biomedical Data Sciences, Section of Molecular Epidemiology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [50 ]GRID grid.5603.0, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, ; Greifswald, Germany
                [51 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, Medical School, , University of Western Australia, ; Crawley, WA 6009 Australia
                [52 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Medicine, Cardiovascular Health Research Unit, , University of Washington, ; Seattle, WA USA
                [53 ]GRID grid.5963.9, Faculty of Biology, University of Freiburg, ; Freiburg, Germany
                [54 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Cardiology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [55 ]ISNI 0000000089452978, GRID grid.10419.3d, Einthoven Laboratory for Experimental Vascular Medicine, LUMC, ; Leiden, The Netherlands
                [56 ]ISNI 0000 0004 0632 3062, GRID grid.424592.c, Children’s Hospital, Helsinki University Hospital and University of Helsinki, ; Helsinki, Finland
                [57 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, PEDEGO Research Unit, , MRC Oulu, Oulu University Hospital and University of Oulu, ; Oulu, Finland
                [58 ]ISNI 0000 0004 0372 2033, GRID grid.258799.8, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, ; Kyoto, Japan
                [59 ]GRID grid.417834.d, Institute of Epidemiology, Friedrich-Loeffler-Institut (FLI), Federal Research Institute for Animal Health, ; Greifswald, Germany
                [60 ]ISNI 0000 0004 0626 3303, GRID grid.410566.0, Department of Endocrinology, , Ghent University Hospital, ; Ghent, Belgium
                [61 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Rheumatology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [62 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Clinical Epidemiology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [63 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Department of Medical Genetics, Division of Genetic Epidemiology, Molecular and Clinical Pharmacology, , Medical University of Innsbruck, ; Innsbruck, Austria
                [64 ]Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
                [65 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Department of Biostatistics, , Boston University, ; Boston, MA USA
                [66 ]GRID grid.475435.4, Department of Clinical Experimental Research, , Rigshospitalet, ; Copenhagen, Denmark
                [67 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, Department of Computational Biology, Graduate School of Frontier Sciences, , The University of Tokyo, ; Tokyo, Japan
                [68 ]ISNI 0000 0001 0679 2801, GRID grid.9018.0, Institute for Medical Epidemiology, Biostatistics and Informatics, , Martin-Luther-University Halle-Wittenberg, ; Halle, Germany
                [69 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Chair of Epidemiology, , Ludwig-Maximilians-Universität München, at UNIKA-T Augsburg, ; Augsburg, Germany
                [70 ]ISNI 0000 0001 2069 7798, GRID grid.5342.0, Department of Data Analysis and Mathematical Modelling, , Ghent University, ; Ghent, Belgium
                [71 ]ISNI 0000 0004 1937 0642, GRID grid.6612.3, Department of Pharmaceutical Sciences, , University of Basel, ; Basel, Switzerland
                [72 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Internal Medicine, Division of Endocrinology, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [73 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Epidemiology, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [74 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Statistical Genetics, , Osaka University Graduate School of Medicine, ; Osaka, Japan
                [75 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), , Osaka University, ; Suita, Japan
                [76 ]GRID grid.5603.0, Institute of Clinical Chemistry and Laboratory Medicine, , University Medicine Greifswald, ; Greifswald, Germany
                [77 ]ISNI 0000 0001 2165 4204, GRID grid.9851.5, Center for Integrative Genomics, , University of Lausanne, and Swiss Institute of Bioinformatics, ; 1015 Lausanne, Switzerland
                [78 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Internal Medicine, , Section of Gerontology and Geriatrics, Leiden University Medical Center, ; Leiden, Netherlands
                [79 ]ISNI 0000000122986657, GRID grid.34477.33, Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, , University of Washington, ; Seattle, WA USA
                [80 ]ISNI 0000 0004 0615 7519, GRID grid.488833.c, Kaiser Permanente Washington Health Research Institute, ; Seattle, WA USA
                [81 ]ISNI 0000 0000 9401 2774, GRID grid.414980.0, Lady Davis Institute, , Jewish General Hospital, ; Montreal, QC H3T 1E2 Canada
                [82 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, The Department of Twin Research and Genetic Epidemiology, , King’s College London, St. Thomas’ Campus, ; Lambeth Palace Road, London, SE1 7EH UK
                [83 ]ISNI 0000 0004 0626 3303, GRID grid.410566.0, Biobanking and Cardiovascular Epidemiology, , Ghent University Hospital, ; Ghent, Belgium
                [84 ]ISNI 0000 0001 2069 7798, GRID grid.5342.0, Department of Internal Medicine (Cardiology), , Ghent University, ; Ghent, Belgium
                [85 ]ISNI 0000 0001 0157 6501, GRID grid.239844.0, The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, , LABioMed at Harbor-UCLA Medical Center, ; Torrance, CA USA
                [86 ]ISNI 0000 0000 9372 4913, GRID grid.419475.a, Laboratory of Genetics and Genomics, , National Institute on Aging, National Institutes of Health, ; Baltimore, MD USA
                [87 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Epidemiology, Welch Center for Prevention, Epidemiology and Clinical Research, , Johns Hopkins Bloomberg School of Public Health, ; Baltimore, MD USA
                [88 ]ISNI 0000 0004 0606 5382, GRID grid.10306.34, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, ; Cambridge, CB10 1HH UK
                [89 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Department of Public Health (Section on Epidemiology), Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark
                [90 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Alzheimer Scotland Dementia Research Centre, , University of Edinburgh, ; Edinburgh, UK
                [91 ]ISNI 0000 0001 2193 314X, GRID grid.8756.c, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, ; Glasgow, UK
                [92 ]ISNI 0000 0004 0626 3792, GRID grid.420036.3, AZ Sint Jan Brugge, ; Brugge, Belgium
                [93 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Endocrinology, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [94 ]GRID grid.494629.4, Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University and Westlake Institute for Advanced Study, ; Hangzhou, Zhejiang China
                [95 ]ISNI 0000 0001 2230 9154, GRID grid.410595.c, Institute of Aging Research and the Affiliated Hospital, School of Medicine, Hangzhou Normal University, ; Hangzhou, Zhejiang China
                [96 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Division of Endocrinology, Diabetes, and Metabolism, , University of Pennsylvania School of Medicine, ; Philadelphia, PA USA
                [97 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Genetics, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [98 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Epidemiology, , Johns Hopkins Bloomberg School of Public Health, ; 625 N Wolfe Street, Baltimore, MD 21205 USA
                [99 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Epidemiology, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [100 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Genetics, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [101 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Cardiology, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [102 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Internal Medicine, Division of Nephrology, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [103 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Pathology and Medical Biology, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                Article
                6356
                10.1038/s41467-018-06356-1
                6203810
                30367059
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: The list of funders and grants is provided in the Supplementary Note 4 of the Supplementary Information.
                Categories
                Article
                Custom metadata
                © The Author(s) 2018

                Uncategorized

                Comments

                Comment on this article