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

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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.

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Fig. 1: Trans-ancestry GWAS meta-analysis identifies 183 loci associated with serum urate.
Fig. 2: A GRS for serum urate improves gout risk prediction.
Fig. 3: Serum urate shows widespread genetic correlations with cardiometabolic risk factors and diseases.
Fig. 4: Genes expressed in urate-associated loci are enriched in kidney tissue and pathways.
Fig. 5: Prioritization of p.Thr139Ile at HNF4A and functional study of HNF4A regulation of ABCG2 transcription.
Fig. 6: Colocalization of urate association signals with gene expression in cis in kidney tissues.

Data availability

Genome-wide summary statistics for this study are available at the CKDGen Consortium (http://ckdgen.imbi.uni-freiburg.de) and will be made publicly available through the database of Genotypes and Phenotypes accession no. phs000930.v6.p1.

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Acknowledgements

We thank D. Di Domizio (Eurac Research) and J. Knaus (University of Freiburg) for IT assistance, and T. Johnson (GlaxoSmithKline) for sharing his code and for the discussion about fine-mapping a credible set and the colocalization analysis. This research was conducted using the UKBB Resource (application no. 20272). Study-specific acknowledgements and funding sources are listed in the Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health (NIH) or the US Department of Health and Human Services.

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A.Tin, J.M., V.L.H.K., Y.L., M.Wuttke, H.K., K.B.S., C.Q., M.Gorski, M.Scholz, A.M.H., A.Teumer, C.P., O.M.W., V.V. and A.Köttgen wrote the manuscript. A.Tin, J.M., M.Wuttke, M.Gorski, C.F., A.Teumer, C.P., O.M.W., V.V. and A.Köttgen designed the study. A.S.B., A.M.H., A.Teumer, A.P., A.P.J.D.V., A.B.Z., A.D.G., A.Metspalu, A.A.H., A.Tönjes, A.Köttgen, A.P., A.Krajčoviechová, A.R., A.C., B.Ponte, B.K.K., B.J., B.W.J.H.P., B.M.P., C.H., C.A.B., C.N.S., C.G., C.J.O.D., C.M.V.D., C.P., D.T., D.C., D.M., E.B., E.I., F.K., G.S., G.E., G.W., G.B., G.N.N., G.W.M., H.S., H.Schmidt, I.R., J.M.G., J.F.W., J.G.W., J.S.K., J.O.C., J.Thiery, J.Tremblay, J.B.W., J.C.C., J.C., K.-U.E., K.L.M., K.Stefansson, K.Ho, K.M., K.Strauch, M.A.I., M.E.K., M.C., M.P., M.L., M.Scholz, M.H.D.B., M.Waldenberger, M.Stumvoll, M.K.E., M.K., M. Kähönen, M.B., M.R., N.G.M., O.D., O.T.R., O.P., P.G., P.P.P., P.V., P.V.D.H., Q.Y., R.C., R.Rettig, R.S., R.D.M., R.J.C., R.T.G., R.J.F.L., S.A.P., S.H.W., S.J.L.B., T.B.H., T.L., T.Perls, T.J.R., U.V., V.Giedraitis, V.Gudnason, W.Z., W.Kiess, W.M., W.Koenig, Y. L. and Y.M. managed an individual contributing study. A.S.B., A.M.H., A.Tin, A.P., A.P.J.D.V., A.B.Z., A.V.S., A.Teumer, A.G.U., A.Tönjes, A.Köttgen, A.P., A.H., A.Körner, A.Krajčoviechová, A.R., A.Mahajan, A.Y.C., A.G., B.K.K., B.J., B.N., B.Prins, B.W.J.H.P., B.K., B.M.P., C.H., C.A.B., C.N.S., C.Q., C.M., C.F., C.G., C.J.O.D., C.P., D.F.G., D.R., D.M., D.O.M.-K., E.I., E.P.B., E.Catamo, F.K., G.S., G.B., G.G., G.N.N., G.D., G.W.M., H.S., H.C., H.J., H.H., I.R., I.M.N., I.J., I.M.H., J.F.W., J.G.W., J.J., J.Tremblay, J.B.W., J.M., J.C., K.-U.E., K.L.M., K.E., K.B.S., K.Susztak, K.M.R., K.Ho, K.N., K.Strauch, L.M.R., L.-P.L., L.A.L., L.J.O.C., M.L., M.E.K., M.Ciullo, M.L., M.Scholz, M.H.D.B., M.La Bianca, M.M.-N., M.L.Biggs, M.Gorski, M.N., M.Wuttke, M.Waldenberger, M.H.P., M.K.E., M.Kähönen, M.A.N., M.R., N.G.M., N.V., N.H.-K., N.B., O.D., O.T.R., O.D.W., O.P., P.S., P.H., P.K.J., P.V.D.H., Q.Y., R.C., R.Rettig, R.M.L., R.N., R.D.M., R.J.F.L., S.G., S.C.F., S.M.T., S.S., S.A.P., S.H.W., S.D.G., S.-J.H., S.M.K., S.J.L.B., T.B.H., T.N., T.L., T.S.B., T.M., T.L.E., T.J.R., U.T., U.V., V.V., W.H., W.M., W.Koenig, Y.L. and Z.Y. critically reviewed the manuscript. A.V.S., A.Teumer, A. Tin, A.Köttgen, A.H., A.Mahajan, A.Y.C., A.D., A.G., B.J., B.N., B.Prins, B.K., C.A.B., C.N.S., C.Q., C.H.L.T., C.F., C.P., D.N., D.F.G., E.H., E.S., F.R., G.S., G.B., G.D., H.K., I.M.N., I.M.H., J.J., J.Tremblay, J.M., J.L., K.B.S., K.Susztak, K.A.R., K.Horn, K.M.R., L.M.R., L.-P.L., L.A.L., M.L., M.Brumat, M.E.K., M.P.C., M.Scholz, M.Gögele, M.L.Biggs, M.Kanai, M.A., M.Cocca, M.Gorski, M.N., M.Wuttke, M.H.P., M.A.N., M.R., N.S.J., N.P., N.V., N.M., P.P.M., P.H., P.J.V.D.M., P.K.J., P.V.D.H., Q.Y., R.N., R.Rueedi, R.J.C., S.G., S.M.T., S.S., S.A.P., S.-J.H., T.C., T.N., T.S.B., T.L.E., T.H., V.V., W.Z., W.M., Y.S., Y.X., Y.K., Y.L. and Y.O. carried out the statistical methods and analysis. A.P.J.D.V., A.B.Z., A.Teren, A.Metspalu, A.Tönjes, A.K., A.C., B.Ponte, B.J., B.H.S., B.W.J.H.P., C.A.B., C.M., C.P., D.R., D.C., D.J.P., E.P.B., F.K., G.W., H.C., H.J., I.R., I.O., J.F.W., J.G.W., J.S.K., J.Ä., J.Tremblay, J.B.W., J.C.C., K.D., K.N., K.M., M.Ciullo, M.K.E., M.K., M.Kähönen, M.R., N.G.M., N.H.-K., O.T.R., O.P., P.S., P.V., R.S., R.D.M., R.T.G., S.A., S.P., S.A.P., S.H.W., S.V., T.Poulain, T.L., T.J.R., V.Gudnason, W.H. and W.M. recruited the participants. A.V.S., A.K., A.H., A.Y.C., A.G., B.L., B.Prins, C.A.B., C.N.S., C.Q., C.M.S., D.B., D.O.M.-K., E.H., E.Campana, E.S., F.R., G.E., G.P., H.K., I.M.H., J.F.W., J.J., J.Tremblay, J.M., K.L.M., K.B.S., K.Susztak, K.Horn, L.-P.L., M.L., M.E.K., M.P.C., M.Scholz, M.Cocca, M.Gorski, M.Wuttke, M.H.P., N.S.J., N.P., P.P.M., P.H., P.J.V.D.M., R.N., R.M., R.Rueedi, R.J.C., S.G., S.S., S.A.P., S.D.G., S.B., T.C., T.N., W.Z., W.M., Y.S., Y.X., Y.L., Y. M. and Z.Y. carried out the bioinformatics analysis. A.Tin, A.Teumer, A.G.U., A.K., A.G., B.J., C.A.B., C.N.S., C.Q., C.G., C.J.O.D., C.P., H.J., H.K., I.M.H., J.Tremblay, J.M., K.L.M., K.E., K.B.S., K.D., K.Susztak, K.Horn, K.Ho, L.J.O.C., M.L., M.Scholz, M.Gorski, M.Wuttke, M.R., N.V., O.M.W., P.H, P.V.D.H., S.G., S.S., S.A.P., S.-J.H., V.V., V.L.H.K., W.H., W.Koenig, Y.X. and Y.L. interpreted the results. A.B.Z., A.Teumer, A.G.U., A.Köttgen, A.C., A.D., B.H.S., B.W.J.H.P., C.H., C.A.B., C.N.S., C.F., C.M.V.D., D.B., D.R., D.T., D.J.P., D.O.M.-K., E.I., E.S., F.R., F.K., G.E., G.W.M., H.C., J.F.W., J.G.W., J.S.K., J.Ä., J.Tremblay, J.C.C., K.L.M., L.-P.L., L.A.L., M.E.K., M.Waldenberger, M.H.P., M.K.E., M.K., M.Kähönen, M.A.N., N.A., N.M., O.T.R., P.S., P.H., P.K., P.V.D.H., R.B., R.T.G., S.M.T., S.P., S.D.G., S.V., T.L., T.M., U.V., W.H., W.M., W.Koenig, and Y.M. carried out the genotyping. V.H.K., R.L. and O.M.W. carried out the functional study.

Correspondence to Adrienne Tin or Anna Köttgen.

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Competing interests

D.O.M.-K. works as a part-time clinical research consultant for METABOLON. B.W.J.H.P. has received research funding (unrelated to the work reported in this article) from Jansen Research and Boehringer Ingelheim. K.B.S is full-time employee of GlaxoSmithKline. G.S., D.F.G., I.J., H.H., P.S., U.T. and K.Stefansson are full time employees of deCODE genetics and Amgen. A.Y.C. is an employee of Merck & Co. W.Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor Pharmaceuticals, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. D.C. is scientific consultant for Bio4Dreams. W.M. is employed by Synlab Services GmbH and holds shares of Synlab Holding Deutschland GmbH. M.A.N.’s participation in this project is supported by a consulting contract between Data Tecnica International, the National Institute on Aging and NIH, and consults or has consulted during this time for Lysosomal Therapeutics, Neuron23, Illumina, the Michael J. Fox Foundation and the University of California Healthcare. O.P. is an owner of Gen-info. K.Ho has disclosed a research and financial relationship with Sanofi Genzyme. B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll Lifecor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. A.S.B. received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. F.R. is a scientific consultant for ePhood. M.Scholz consults for and received grant support not related to this project from Merck Serono. A.Köttgen received grant support not related to this project from Grünenthal. The other authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Note and Figs. 1–8

Reporting Summary

Supplementary Dataset

Regional association plots of 183 genome‐wide significant loci from trans‐ethnic meta‐analysis.

Supplementary Tables

Supplementary Tables 1–22

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