Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

Anna Köttgen, Eva Albrecht, Alexander Teumer, Veronique Vitart, Jan Krumsiek, Claudia Hundertmark, Giorgio Pistis, Daniela Ruggiero, Conall M. O'Seaghdha, Toomas Haller, Qiong Yang, Toshiko Tanaka, Andrew D. Johnson, Zoltán Kutalik, Albert V. Smith, Julia Shi, Maksim Struchalin, Rita P.S. Middelberg, Morris J. Brown, Angelo L. GaffoNicola Pirastu, Guo Li, Caroline Hayward, Tatijana Zemunik, Jennifer Huffman, Loic Yengo, Jing Hua Zhao, Ayse Demirkan, Mary F. Feitosa, Xuan Liu, Giovanni Malerba, Lorna M. Lopez, Pim Van Der Harst, Xinzhong Li, Marcus E. Kleber, Andrew A. Hicks, Ilja M. Nolte, Asa Johansson, Federico Murgia, Sarah H. Wild, Stephan J.L. Bakker, John F. Peden, Abbas Dehghan, Maristella Steri, Albert Tenesa, Vasiliki Lagou, Perttu Salo, Massimo Mangino, Lynda M. Rose, Terho Lehtimäki, Owen M. Woodward, Yukinori Okada, Adrienne Tin, Christian Müller, Christopher Oldmeadow, Margus Putku, Darina Czamara, Peter Kraft, Laura Frogheri, Gian Andri Thun, Anne Grotevendt, Gauti Kjartan Gislason, Tamara B. Harris, Lenore J. Launer, Patrick McArdle, Alan R. Shuldiner, Eric Boerwinkle, Josef Coresh, Helena Schmidt, Michael Schallert, Nicholas G. Martin, Grant W. Montgomery, Michiaki Kubo, Yusuke Nakamura, Toshihiro Tanaka, Patricia B. Munroe, Nilesh J. Samani, David R. Jacobs, Kiang Liu, Pio D'Adamo, Sheila Ulivi, Jerome I. Rotter, Bruce M. Psaty, Peter Vollenweider, Gerard Waeber, Susan Campbell, Olivier Devuyst, Pau Navarro, Ivana Kolcic, Nicholas Hastie, Beverley Balkau, Philippe Froguel, Tõnu Esko, Andres Salumets, Kay Tee Khaw, Claudia Langenberg, Nicholas J. Wareham, Aaron Isaacs, Aldi Kraja, Qunyuan Zhang, Philipp S. Wild, Rodney J. Scott, Elizabeth G. Holliday, Elin Org, Margus Viigimaa, Stefania Bandinelli, Jeffrey E. Metter, Antonio Lupo, Elisabetta Trabetti, Rossella Sorice, Angela Döring, Eva Lattka, Konstantin Strauch, Fabian Theis, Melanie Waldenberger, H. Erich Wichmann, Gail Davies, Alan J. Gow, Marcel Bruinenberg, Ronald P. Stolk, Jaspal S. Kooner, Weihua Zhang, Bernhard R. Winkelmann, Bernhard O. Boehm, Susanne Lucae, Brenda W. Penninx, Johannes H. Smit, Gary Curhan, Poorva Mudgal, Robert M. Plenge, Laura Portas, Ivana Persico, Mirna Kirin, James F. Wilson, Irene Mateo Leach, Wiek H. Van Gilst, Anuj Goel, Halit Ongen, Albert Hofman, Fernando Rivadeneira, Andre G. Uitterlinden, Medea Imboden, Arnold Von Eckardstein, Francesco Cucca, Ramaiah Nagaraja, Maria Grazia Piras, Matthias Nauck, Claudia Schurmann, Kathrin Budde, Florian Ernst, Susan M. Farrington, Evropi Theodoratou, Inga Prokopenko, Michael Stumvoll, Antti Jula, Markus Perola, Veikko Salomaa, So Youn Shin, Tim D. Spector, Cinzia Sala, Paul M. Ridker, Mika Kähönen, Jorma Viikari, Christian Hengstenberg, Christopher P. Nelson, James F. Meschia, Michael A. Nalls, Pankaj Sharma, Andrew B. Singleton, Naoyuki Kamatani, Tanja Zeller, Michel Burnier, John Attia, Maris Laan, Norman Klopp, Hans L. Hillege, Stefan Kloiber, Hyon Choi, Mario Pirastu, Silvia Tore, Nicole M. Probst-Hensch, Henry Völzke, Vilmundur Gudnason, Afshin Parsa, Reinhold Schmidt, John B. Whitfield, Myriam Fornage, Paolo Gasparini, David S. Siscovick, Ozren Polašek, Harry Campbell, Igor Rudan, Nabila Bouatia-Naji, Andres Metspalu, Ruth J.F. Loos, Cornelia M. Van Duijn, Ingrid B. Borecki, Luigi Ferrucci, Giovanni Gambaro, Ian J. Deary, Bruce H.R. Wolffenbuttel, John C. Chambers, Winfried März, Peter P. Pramstaller, Harold Snieder, Ulf Gyllensten, Alan F. Wright, Gerjan Navis, Hugh Watkins, Jacqueline C.M. Witteman, Serena Sanna, Sabine Schipf, Malcolm G. Dunlop, Anke Tönjes, Samuli Ripatti, Nicole Soranzo, Daniela Toniolo, Daniel I. Chasman, Olli Raitakari, W. H.Linda Kao, Marina Ciullo, Caroline S. Fox, Mark Caulfield, Murielle Bochud, Christian Gieger

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Abstract

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

Original languageEnglish
Pages (from-to)145-154
Number of pages10
JournalNature Genetics
Volume45
Issue number2
DOIs
Publication statusPublished - 01-02-2013

All Science Journal Classification (ASJC) codes

  • Genetics

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    Köttgen, A., Albrecht, E., Teumer, A., Vitart, V., Krumsiek, J., Hundertmark, C., Pistis, G., Ruggiero, D., O'Seaghdha, C. M., Haller, T., Yang, Q., Tanaka, T., Johnson, A. D., Kutalik, Z., Smith, A. V., Shi, J., Struchalin, M., Middelberg, R. P. S., Brown, M. J., ... Gieger, C. (2013). Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nature Genetics, 45(2), 145-154. https://doi.org/10.1038/ng.2500