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

Tin, A. et al. (2019) Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. Nature Genetics, 51, pp. 1459-1474. (doi: 10.1038/s41588-019-0504-x) (PMID:31578528)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Padmanabhan, Professor Sandosh
• Authors: 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., Noce, D., Akiyama, M., Cocca, M., Ghasemi, S., van der Most, P. J., Horn, K., Xu, Y., Fuchsberger, C., Sedaghat, S., Afaq, S., Amin, N., Ärnlöv, J., Bakker, S. J. L., Bansal, N., Baptista, D., Bergmann, S., Biggs, M. L., Biino, G., Boerwinkle, E., Bottinger, E. P., Boutin, T. S., Brumat, M., Burkhardt, R., Campana, E., Campbell, A., Campbell, H., Carroll, R. J., Catamo, E., Chambers, J. C., Ciullo, M., Concas, M. P., Coresh, J., Corre, T., Cusi, D., Felicita, S. C., de Borst, M. H., De Grandi, A., de Mutsert, R., de Vries, A. P. J., Delgado, G., Demirkan, A., Devuyst, O., Dittrich, K., Eckardt, K.-U., Ehret, G., Endlich, K., Evans, M. K., Gansevoort, R. T., Gasparini, P., Giedraitis, V., Gieger, C., Girotto, G., Gögele, M., Gordon, S. D., Gudbjartsson, D. F., Gudnason, V., Haller, T., Hamet, P., Harris, T. B., Hayward, C., Hicks, A. A., Hofer, E., Holm, H., Huang, W., Hutri-Kähönen, N., Hwang, S.-J., Ikram, M. A., Lewis, R. M., Ingelsson, E., Jakobsdottir, J., Jonsdottir, I., Jonsson, H., Joshi, P. K., Josyula, N. S., Jung, B., Kähönen, M., Kamatani, Y., Kanai, M., Kerr, S. M., Kiess, W., Kleber, M. E., Koenig, W., Kooner, J. S., Körner, A., Kovacs, P., Krämer, B. K., Kronenberg, F., Kubo, M., Kühnel, B., La Bianca, M., Lange, L. A., Lehne, B., Lehtimäki, T., Liu, J., Loeffler, M., Loos, R. J. F., Lyytikäinen, L.-P., Magi, R., Mahajan, A., Martin, N. G., März, W., Mascalzoni, D., Matsuda, K., Meisinger, C., Meitinger, T., Metspalu, A., Milaneschi, Y., O'Donnell, C. J., Wilson, O. D., Gaziano, J. M., Mishra, P. P., Mohlke, K. L., Mononen, N., Montgomery, G. W., Mook-Kanamori, D. O., Müller-Nurasyid, M., Nadkarni, G. N., Nalls, M. A., Nauck, M., Nikus, K., Ning, B., Nolte, I. M., Noordam, R., O'Connell, J. R., Olafsson, I., Padmanabhan, S., Penninx, B. W. J. H., Perls, T., Peters, A., Pirastu, M., Pirastu, N., Pistis, G., Polasek, O., Ponte, B., Porteous, D. J., Poulain, T., Preuss, M. H., Rabelink, T. J., Raffield, L. M., Raitakari, O. T., Rettig, R., Rheinberger, M., Rice, K. M., Rizzi, F., Robino, A., Rudan, I., Krajcoviechova, A., Cifkova, R., Rueedi, R., Ruggiero, D., Ryan, K. A., Saba, Y., Salvi, E., Schmidt, H., Schmidt, R., Shaffer, C. M., Smith, A. V., Smith, B. H., Spracklen, C. N., Strauch, K., Stumvoll, M., Sulem, P., Tajuddin, S. M., Teren, A., Thiery, J., Thio, C. H. L., Thorsteinsdottir, U., Toniolo, D., Tönjes, A., Tremblay, J., Uitterlinden, A. G., Vaccargiu, S., van der Harst, P., van Duijn, C. M., Verweij, N., Völker, U., Vollenweider, P., Waeber, G., Waldenberger, M., Whitfield, J. B., Wild, S. H., Wilson, J. F., Yang, Q., Zhang, W., Zonderman, A. B., Bochud, M., Wilson, J. G., Pendergrass, S. A., Ho, K., Parsa, A., Pramstaller, P. P., Psaty, B. M., Böger, C. A., Snieder, H., Butterworth, A. S., Okada, Y., Edwards, T. L., Stefansson, K., Susztak, K., Scholz, M., Heid, I. M., Hung, A. M., Teumer, A., Pattaro, C., Woodward, O. M., Vitart, V., and Köttgen, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Nature Genetics
• Publisher: Nature Publishing Group
• ISSN: 1061-4036
• ISSN (Online): 1546-1718
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Nature Genetics 51:1459-1474
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher