Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus
Year: 2021
Type: article
Study design: Observational Study
Abstract: Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
Source: Nature Communications
Authors: Adrienne Tin, Pascal Schlosser, Pamela R. Matias-Garcia, Chris H. L. Thio, Roby Joehanes, Hongbo Liu, Zhi Yu, Antoine Weihs, Anselm Hoppmann, Franziska Grundner-Culemann, Josine L. Min, Victoria L. Halperin Kuhns, Adebowale A. Adeyemo, Charles Agyemang, Johan Ärnlöv, Nasir A. Aziz, Andrea Baccarelli, Murielle Bochud, Hermann Brenner, Jan Bressler, Monique M. B. Breteler, Cristian Carmeli, Layal Chaker, Josef Coresh, Tanguy Corre, Adolfo Correa, Simon R. Cox, Graciela E. Delgado, Kai-Uwe Eckardt, Arif B. Ekici, Karlhans Endlich, James S. Floyd, Eliza Fraszczyk, Xu Gao, Xīn Gào, Allan C. Gelber, Mohsen Ghanbari, Sahar Ghasemi, Christian Gieger, Philip Greenland, Megan L. Grove, Sarah E. Harris, Gibran Hemani, Peter Henneman, Christian Herder, Steve Horvath, Lifang Hou, Mikko A. Hurme, Shih-Jen Hwang, Sharon L. R. Kardia, Silva Kasela, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Florian Kronenberg, Brigitte Kühnel, Christine Ladd-Acosta, Terho Lehtimäki, Lars Lind, Dan Liu, Donald M. Lloyd-Jones, Stefan Lorkowski, Ake T. Lu, Riccardo E. Marioni, Winfried März, Daniel L. McCartney, Karlijn A. C. Meeks, Lili Milani, Pashupati P. Mishra, Matthias Nauck, Christoph Nowak, Annette Peters, Holger Prokisch, Bruce M. Psaty, Olli T. Raitakari, Scott M. Ratliff, Alex P. Reiner, Ben Schöttker, Joel Schwartz, Sanaz Sedaghat, Jennifer A. Smith, Nona Sotoodehnia, Hannah R. Stocker, Silvia Stringhini, Johan Sundström, Brenton R. Swenson, Joyce B. J. van Meurs, Jana V. van Vliet-Ostaptchouk, Andrea Venema, Uwe Völker, Juliane Winkelmann, Bruce H. R. Wolffenbuttel, Wei Zhao, Yinan Zheng, Marie Loh, Harold Snieder, Melanie Waldenberger, Daniel Levy, Shreeram Akilesh, Owen M. Woodward, Katalin Susztak, Alexander Teumer, Anna Köttgen
Institutions: Johns Hopkins University, University of Mississippi Medical Center, University of Freiburg, Helmholtz Munich, Technical University of Munich, University Medical Center Groningen, University of Groningen, National Institutes of Health, National Heart, Lung, and Blood Institute, Framingham Heart Study, University of Pennsylvania, Broad Institute, Massachusetts General Hospital, Universitätsmedizin Greifswald, Universität Greifswald, University of Bristol, MRC Integrative Epidemiology Unit, University of Maryland, Baltimore, National Human Genome Research Institute, Amsterdam Public Health, Amsterdam University Medical Centers, University of Amsterdam, Dalarna University, Karolinska Institutet, University of Bonn, German Center for Neurodegenerative Diseases, Columbia University, Centre universitaire de médecine générale et santé publique, Lausanne, University of Lausanne, German Cancer Research Center, Heidelberg University, National Center for Tumor Diseases, The University of Texas Health Science Center at Houston, Institut für Medizinische Biometrie, Informatik und Epidemiologie, University of Fribourg, Erasmus MC, University of Edinburgh, Medizinische Fakultät Mannheim, Friedrich-Alexander-Universität Erlangen-Nürnberg, Charité - Universitätsmedizin Berlin, German Centre for Cardiovascular Research, University of Washington, Peking University, Johns Hopkins Medicine, Northwestern University, Amsterdam Reproduction Development, Deutsches Diabetes-Zentrum e.V., German Center for Diabetes Research, Heinrich Heine University Düsseldorf, University of California, Los Angeles, Tampere University, University of Tampere, University of Michigan, University of Tartu, Universität Ulm, Deutsches Herzzentrum München, Imperial College Healthcare NHS Trust, Ealing Hospital, London North West Healthcare NHS Trust, Imperial College London, Innsbruck Medical University, Universität Innsbruck, Fimlab (Finland), Uppsala University, Friedrich Schiller University Jena, Institute of Genetics and Cancer, Medical University of Graz, Synlab (Germany), Ludwig-Maximilians-Universität München, TUM Klinikum, Institut für Humangenetik, University of Turku, Turku University Hospital, Harvard University, University of Minnesota, Institute for Social Research, UNSW Sydney, The George Institute for Global Health, Munich Cluster for Systems Neurology, Nanyang Technological University, Medical University of Białystok
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,813
OpenAlex ID: W4200137222