Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

作者：German Chronic Kidney Disease Study, Adrienne Tin, Lifelines Cohort Study, V. A. Million Veteran Program, Jonathan Marten, Victoria L. Halperin Kuhns, Yong Li, Matthias Wuttke, Holger Kirsten, Karsten B. Sieber, Chengxiang Qiu, Mathias Gorski, Zhi Yu, Ayush Giri, Garðar Sveinbjörnsson, Man Li, Audrey Y. Chu, Anselm Hoppmann, Luke J. O’Connor, Bram P. Prins, Teresa Nutile, Damia Noce, Masato Akiyama, Massimiliano Cocca, Sahar Ghasemi, Peter J. van der Most, Katrin Horn, Yizhe Xu, Christian Fuchsberger, Sanaz Sedaghat, Saima Afaq, Najaf Amin, Johan Ärnlöv, Stephan J. L. Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L. Biggs, Ginevra Biino, Eric Boerwinkle, Erwin P. Böttinger, Thibaud Boutin, Marco Brumat, Ralph Burkhardt, Eric Campana, Archie Campbell, Harry Campbell, Robert J. Carroll, Eulalia Catamo, John C. Chambers, Marina Ciullo, Maria Pina Concas, Josef Coresh, Tanguy Corre, Daniele Cusi, Cinzia Sala, Martin H. de Borst, Alessandro De Grandi, Renée de Mutsert, Aiko P. J. de Vries, Graciela Delgado, Ayşe Demirkan, Olivier Devuyst, Katalin Dittrich, Kai‐Uwe Eckardt, Georg Ehret, Karlhans Endlich, Michele K. Evans, Ron T. Gansevoort, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Martin Gögele, Scott D. Gordon, Daníel F. Guðbjartsson, Vilmundur Guðnason, Toomas Haller, Pavel Hamet, Tamara B. Harris, Caroline Hayward, Andrew A. Hicks, Edith Hofer, Hilma Hólm, Wei Huang, Nina Hutri‐Kähönen, Shih‐Jen Hwang, M. Arfan Ikram, Raychel M. Lewis, Erik Ingelsson, Jóhanna Jakobsdóttir, Ingileif Jónsdóttir, Helgi Jónsson, Peter K. Joshi, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Shona M. Kerr, Wieland Kieß, Marcus E. Kleber, Wolfgang Köenig, Jaspal S. Kooner, Antje Körner, Péter Kovács, Bernhard K. Krämer, Florian Kronenberg, Michiaki Kubo, Brigitte Kühnel, Martina La Bianca, Leslie A. Lange, Benjamin Lehne, Terho Lehtimäki, Jun Liu, Markus Loeffler, Ruth J. F. Loos, Leo‐Pekka Lyytikäinen, Reedik Mägi, Anubha Mahajan, Nicholas G. Martin, Winfried März, Deborah Mascalzoni, Koichi Matsuda, Christa Meisinger, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Christopher J. O’Donnell, Otis D. Wilson, J. Michael Gaziano, Pashupati P. Mishra, Karen L. Mohlke, Nina Mononen, Grant W. Montgomery, Dennis O. Mook‐Kanamori, Martina Müller‐Nurasyid, Girish N. Nadkarni, Mike A. Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M. Nolte, Raymond Noordam, Jeffrey R. O’Connell, Ísleifur Ólafsson, Sandosh Padmanabhan, Brenda W.J.H. Penninx, Thomas T. Perls, Annette Peters, Mario Pirastu, Nicola Pirastu, Giorgio Pistis, Ozren Polašek, Belén Ponte, David J. Porteous, Tanja Poulain, Michael Preuß, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Rainer Rettig, Myriam Rheinberger, Kenneth Rice, Federica Rizzi, Antonietta Robino, Igor Rudan, Alena Krajčoviechová, Renata Cífková, Rico Rueedi, Daniela Ruggiero, Kathleen A. Ryan, Yasaman Saba, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Christian M. Shaffer, Albert V. Smith, Blair H. Smith, Cassandra N. Spracklen, Konstantin Strauch, Michael Stümvoll, Patrick Sulem, Salman M. Tajuddin, Andrej Teren, Joachim Thiery, Chris H. L. Thio, Unnur Þorsteinsdóttir, Daniela Toniolo, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Simona Vaccargiu, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, Uwe Völker, Péter Vollenweider, Gérard Waeber, Mélanie Waldenberger, John B. Whitfield, Sarah H. Wild, James F. Wilson, Qiong Yang, Weihua Zhang, Alan B. Zonderman, Murielle Bochud, James G. Wilson, Sarah A. Pendergrass, Kevin Ho, Afshin Parsa, Peter P. Pramstaller, Bruce M. Psaty, Carsten A. Böger, Harold Snieder, Adam S. Butterworth, Yukinori Okada, Todd L. Edwards, Kāri Stefánsson, Katalin Suszták, Markus Scholz, Iris M. Heid, Adriana M. Hung, Alexander Teumer, Cristian Pattaro, Owen M. Woodward, Véronique Vitart, Anna Köttgen · 发表于：Nature Genetics · 年份：2019 · DOI：10.1038/s41588-019-0504-x · 被引用次数：442 · 研究领域：Gout, Hyperuricemia, Uric Acid、Liver Disease Diagnosis and Treatment

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. A trans-ancestry genome-wide association study of serum urate levels identifies 183 loci influencing this trait. Enrichment analyses, fine-mapping and colocalization with gene expression in 47 tissues implicate the kidney and liver as key target organs and prioritize potential causal genes.