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Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
Authors :
Tin, Adrienne Marten, Jonathan Kuhns, Victoria L. Halperin Li, Yong Wuttke, Matthias Kirsten, Holger Sieber, Karsten B. Qiu, Chengxiang Gorski, Mathias Yu, Zhi Giri, Ayush Sveinbjornsson, Gardar Li, Man Chu, Audrey Y. Hoppmann, Anselm O'Connor, Luke J. Prins, Bram Nutile, Teresa Noce, Damia Akiyama, Masato Cocca, Massimiliano Ghasemi, Sahar van Der Most, Peter J. Horn, Katrin Xu, Yizhe Fuchsberger, Christian Sedaghat, Sanaz Afaq, Saima Amin, Najaf Arnlov, Johan Bakker, Stephan J. L. Bansal, Nisha Baptista, Daniela Bergmann, Sven Biggs, Mary L. Biino, Ginevra Boerwinkle, Eric Bottinger, Erwin P. Boutin, Thibaud S. Brumat, Marco Burkhardt, Ralph Campana, Eric Campbell, Archie Campbell, Harry Carroll, Robert J. Catamo, Eulalia Chambers, John C. Ciullo, Marina Concas, Maria Pina Coresh, Josef Corre, Tanguy Cusi, Daniele Felicita, Sala Cinzia de Borst, Martin H. De Grandi, Alessandro de Mutsert, Rene de Vries, Aiko P. J. Delgado, Graciela Demirkan, Ayse Devuyst, Olivier Dittrich, Katalin Eckardt, Kai-Uwe Ehret, Georg Endlich, Karlhans Evans, Michele K. Gansevoort, Ron T. Gasparini, Paolo Giedraitis, Vilmantas Gieger, Christian Girotto, Giorgia Ggele, Martin Gordon, Scott D. Gudbjartsson, Daniel F. Gudnason, Vilmundur Haller, Toomas Hamet, Pavel Harris, Tamara B. Hayward, Caroline Hicks, Andrew A. Hofer, Edith Holm, Hilma Huang, Wei Hutri-Kahonen, Nina Hwang, Shih-Jen Ikram, M. Arfan Lewis, Raychel M. Ingelsson, Erik Jakobsdottir, Johanna Jonsdottir, Ingileif Jonsson, Helgi Joshi, Peter K. Josyula, Navya Shilpa Jung, Bettina Kahonen, Mika Kamatani, Yoichiro Kanai, Masahiro Kerr, Shona M. Kiess, Wieland Kleber, Marcus E. Koenig, Wolfgang Kooner, Jaspal S. Korner, Antje Kovacs, Peter Kramer, Bernhard K. Kronenberg, Florian Kubo, Michiaki Kuhnel, Brigitte La Bianca, Martina Lange, Leslie A. Lehne, Benjamin Lehtimaki, Terho Liu, Jun Loeffler, Markus Loos, Ruth J. F. Lyytikainen, Leo-Pekka Magi, Reedik Mahajan, Anubha Martin, Nicholas G. Marz, Winfried Mascalzoni, Deborah Matsuda, Koichi Meisinger, Christa Meitinger, Thomas Metspalu, Andres Milaneschi, Yuri ODonnell, Christopher J. Wilson, Otis D. Gaziano, J. Michael Mishra, Pashupati P. Mohlke, Karen L. Mononen, Nina Montgomery, Grant W. Mook-Kanamori, Dennis O. Mueller-Nurasyid, Martina Nadkarni, Girish N. Nalls, Mike A. Nauck, Matthias Nikus, Kjell Ning, Boting Nolte, Ilja M. Noordam, Raymond O'Connell, Jeffrey R. Olafsson, Isleifur Padmanabhan, Sandosh Penninx, Brenda W. J. H. Perls, Thomas Peters, Annette Pirastu, Mario Pirastu, Nicola Pistis, Giorgio Polasek, Ozren Ponte, Belen Porteous, David J. Poulain, Tanja Preuss, Michael H. Rabelink, Ton J. Raffield, Laura M. Raitakari, Olli T. Rettig, Rainer Rheinberger, Myriam Rice, Kenneth M. Rizzi, Federica Robino, Antonietta Rudan, Igor Krajcoviechova, Alena Cifkova, Renata Rueedi, Rico Ruggiero, Daniela Ryan, Kathleen A. Saba, Yasaman Salvi, Erika Schmidt, Helena Schmidt, Reinhold Shaffer, Christian M. Smith, Albert, V Smith, Blair H. Spracklen, Cassandra N. Strauch, Konstantin Stumvoll, Michael Sulem, Patrick Tajuddin, Salman M. Teren, Andrej Thiery, Joachim Thio, Chris H. L. Thorsteinsdottir, Unnur Toniolo, Daniela Tonjes, Anke Tremblay, Johanne Uitterlinden, Andre G. Vaccargiu, Simona van der Harst, Pim van Duijn, Cornelia M. Verweij, Niek Voelker, Uwe Vollenweider, Peter Waeber, Gerard Waldenberger, Melanie Whitfield, John B. Wild, Sarah H. Wilson, James F. Yang, Qiong Zhang, Weihua Zonderman, Alan B. Bochud, Murielle Wilson, James G. Pendergrass, Sarah A. Ho, Kevin Parsa, Afshin Pramstaller, Peter P. Psaty, Bruce M. Boeger, Carsten A. Snieder, Harold Butterworth, Adam S. Okada, Yukinori Edwards, Todd L. Stefansson, Kari Susztak, Katalin Scholz, Markus Heid, Iris M. Hung, Adriana M. Teumer, Alexander Pattaro, Cristian Woodward, Owen M. Vitart, Veronique Koettgen, Anna Tin, Adrienne Marten, Jonathan Kuhns, Victoria L. Halperin Li, Yong Wuttke, Matthias Kirsten, Holger Sieber, Karsten B. Qiu, Chengxiang Gorski, Mathias Yu, Zhi Giri, Ayush Sveinbjornsson, Gardar Li, Man Chu, Audrey Y. Hoppmann, Anselm O'Connor, Luke J. Prins, Bram Nutile, Teresa Noce, Damia Akiyama, Masato Cocca, Massimiliano Ghasemi, Sahar van Der Most, Peter J. Horn, Katrin Xu, Yizhe Fuchsberger, Christian Sedaghat, Sanaz Afaq, Saima Amin, Najaf Arnlov, Johan Bakker, Stephan J. L. Bansal, Nisha Baptista, Daniela Bergmann, Sven Biggs, Mary L. Biino, Ginevra Boerwinkle, Eric Bottinger, Erwin P. Boutin, Thibaud S. Brumat, Marco Burkhardt, Ralph Campana, Eric Campbell, Archie Campbell, Harry Carroll, Robert J. Catamo, Eulalia Chambers, John C. Ciullo, Marina Concas, Maria Pina Coresh, Josef Corre, Tanguy Cusi, Daniele Felicita, Sala Cinzia de Borst, Martin H. De Grandi, Alessandro de Mutsert, Rene de Vries, Aiko P. J. Delgado, Graciela Demirkan, Ayse Devuyst, Olivier Dittrich, Katalin Eckardt, Kai-Uwe Ehret, Georg Endlich, Karlhans Evans, Michele K. Gansevoort, Ron T. Gasparini, Paolo Giedraitis, Vilmantas Gieger, Christian Girotto, Giorgia Ggele, Martin Gordon, Scott D. Gudbjartsson, Daniel F. Gudnason, Vilmundur Haller, Toomas Hamet, Pavel Harris, Tamara B. Hayward, Caroline Hicks, Andrew A. Hofer, Edith Holm, Hilma Huang, Wei Hutri-Kahonen, Nina Hwang, Shih-Jen Ikram, M. Arfan Lewis, Raychel M. Ingelsson, Erik Jakobsdottir, Johanna Jonsdottir, Ingileif Jonsson, Helgi Joshi, Peter K. Josyula, Navya Shilpa Jung, Bettina Kahonen, Mika Kamatani, Yoichiro Kanai, Masahiro Kerr, Shona M. Kiess, Wieland Kleber, Marcus E. Koenig, Wolfgang Kooner, Jaspal S. Korner, Antje Kovacs, Peter Kramer, Bernhard K. Kronenberg, Florian Kubo, Michiaki Kuhnel, Brigitte La Bianca, Martina Lange, Leslie A. Lehne, Benjamin Lehtimaki, Terho Liu, Jun Loeffler, Markus Loos, Ruth J. F. Lyytikainen, Leo-Pekka Magi, Reedik Mahajan, Anubha Martin, Nicholas G. Marz, Winfried Mascalzoni, Deborah Matsuda, Koichi Meisinger, Christa Meitinger, Thomas Metspalu, Andres Milaneschi, Yuri ODonnell, Christopher J. Wilson, Otis D. Gaziano, J. Michael Mishra, Pashupati P. Mohlke, Karen L. Mononen, Nina Montgomery, Grant W. Mook-Kanamori, Dennis O. Mueller-Nurasyid, Martina Nadkarni, Girish N. Nalls, Mike A. Nauck, Matthias Nikus, Kjell Ning, Boting Nolte, Ilja M. Noordam, Raymond O'Connell, Jeffrey R. Olafsson, Isleifur Padmanabhan, Sandosh Penninx, Brenda W. J. H. Perls, Thomas Peters, Annette Pirastu, Mario Pirastu, Nicola Pistis, Giorgio Polasek, Ozren Ponte, Belen Porteous, David J. Poulain, Tanja Preuss, Michael H. Rabelink, Ton J. Raffield, Laura M. Raitakari, Olli T. Rettig, Rainer Rheinberger, Myriam Rice, Kenneth M. Rizzi, Federica Robino, Antonietta Rudan, Igor Krajcoviechova, Alena Cifkova, Renata Rueedi, Rico Ruggiero, Daniela Ryan, Kathleen A. Saba, Yasaman Salvi, Erika Schmidt, Helena Schmidt, Reinhold Shaffer, Christian M. Smith, Albert, V Smith, Blair H. Spracklen, Cassandra N. Strauch, Konstantin Stumvoll, Michael Sulem, Patrick Tajuddin, Salman M. Teren, Andrej Thiery, Joachim Thio, Chris H. L. Thorsteinsdottir, Unnur Toniolo, Daniela Tonjes, Anke Tremblay, Johanne Uitterlinden, Andre G. Vaccargiu, Simona van der Harst, Pim van Duijn, Cornelia M. Verweij, Niek Voelker, Uwe Vollenweider, Peter Waeber, Gerard Waldenberger, Melanie Whitfield, John B. Wild, Sarah H. Wilson, James F. Yang, Qiong Zhang, Weihua Zonderman, Alan B. Bochud, Murielle Wilson, James G. Pendergrass, Sarah A. Ho, Kevin Parsa, Afshin Pramstaller, Peter P. Psaty, Bruce M. Boeger, Carsten A. Snieder, Harold Butterworth, Adam S. Okada, Yukinori Edwards, Todd L. Stefansson, Kari Susztak, Katalin Scholz, Markus Heid, Iris M. Hung, Adriana M. Teumer, Alexander Pattaro, Cristian Woodward, Owen M. Vitart, Veronique Koettgen, Anna
Publication Year :
2019
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.
Details
Database :
OAIster
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1235233440
Document Type :
Electronic Resource
Full Text :
https://doi.org/10.1038.s41588-019-0504-x