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

, Adrienne Tin (Lead / Corresponding author), 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 NoceMasato 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, Blair H. Smith, Anna Köttgen

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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.

Original languageEnglish
Pages (from-to)1459–1474
Number of pages22
JournalNature Genetics
Volume51
Issue number10
Early online date2 Oct 2019
DOIs
Publication statusPublished - Oct 2019

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    , Tin, A., Marten, J., Halperin Kuhns, V. L., Li, Y., Wuttke, M., Kirsten, H., Sieber, K. B., Qiu, C., Gorski, M., Yu, Z., Giri, A., Sveinbjornsson, G., Li, M., Chu, A. Y., Hoppmann, A., O'Connor, L. J., Prins, B., Nutile, T., ... Köttgen, A. (2019). Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. Nature Genetics, 51(10), 1459–1474 . https://doi.org/10.1038/s41588-019-0504-x