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

Authors:
Adrienne Tin Jonathan Marten Victoria L Halperin Kuhns Yong Li Matthias Wuttke Holger Kirsten Karsten B Sieber Chengxiang Qiu Mathias Gorski Zhi Yu Ayush Giri Gardar Sveinbjornsson Man Li Audrey Y Chu Anselm Hoppmann Luke J O'Connor Bram 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 Bottinger Thibaud S 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 Sala Cinzia Felicita 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 Daniel F Gudbjartsson Vilmundur Gudnason Toomas Haller Pavel Hamet Tamara B Harris Caroline Hayward Andrew A Hicks Edith Hofer Hilma Holm Wei Huang Nina Hutri-Kähönen Shih-Jen Hwang M Arfan Ikram Raychel M Lewis Erik Ingelsson Johanna Jakobsdottir Ingileif Jonsdottir Helgi Jonsson Peter K Joshi Navya Shilpa Josyula Bettina Jung Mika Kähönen Yoichiro Kamatani Masahiro Kanai Shona M Kerr Wieland Kiess Marcus E Kleber Wolfgang Koenig Jaspal S Kooner Antje Körner Peter Kovacs 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 Magi 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 Isleifur Olafsson Sandosh Padmanabhan Brenda W J H Penninx Thomas Perls Annette Peters Mario Pirastu Nicola Pirastu Giorgio Pistis Ozren Polasek Belen Ponte David J Porteous Tanja Poulain Michael H Preuss Ton J Rabelink Laura M Raffield Olli T Raitakari Rainer Rettig Myriam Rheinberger Kenneth M Rice Federica Rizzi Antonietta Robino Igor Rudan Alena Krajcoviechova Renata Cifkova 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 Stumvoll Patrick Sulem Salman M Tajuddin Andrej Teren Joachim Thiery Chris H L Thio Unnur Thorsteinsdottir Daniela Toniolo Anke Tönjes Johanne Tremblay André G Uitterlinden Simona Vaccargiu Pim van der Harst Cornelia M van Duijn Niek Verweij Uwe Völker Peter Vollenweider Gerard Waeber Melanie 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 Kari Stefansson Katalin Susztak Markus Scholz Iris M Heid Adriana M Hung Alexander Teumer Cristian Pattaro Owen M Woodward Veronique Vitart Anna Köttgen

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

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.

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http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019
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