Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

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Abstract

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

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Figure 1: Multiple genomic loci contain SNPs associated with serum urate concentrations.
Figure 2: Minor alleles of all replicated GWAS loci show direction-consistent association with serum urate concentrations and the odds of gout.
Figure 3: SNP effects on urate concentrations (mg/dl) are similar among individuals of European ancestry, African-Americans, Indians and Japanese, whereas allele frequencies vary.

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Acknowledgements

A detailed list of acknowledgments is provided in the Supplementary Note.

Author information

Study design: A. Köttgen, C.G., E.A. and M. Caulfield.

Design and/or management of the individual studies: A.A.H., A. Tenesa, A.F.W., A.L., B.M.P., C.G., D.I.C., D.R., E.G.H., E.O., E. Trabetti, G.C., G.P., H. Campbell, H.-E.W., H. Snieder, I.J.D., J.A., J.C., J.F.W., J.V., L.M.R., M. Ciullo, M. Caulfield, M.F., M. Kubo, M.L., M.V., N.H., N.J.S., N. Kamatani, O.M.W., O.P., O.R., P.B.M., P.D., P.G., P.K., P. Mudgal, P.M.R., P.P.P., P.V., R.M.P., R. Sorice, S.H.W., S.M.F., S.U., T.E., T.L., Toshihiro Tanaka, V.S., W.H.L.K., Y.N., Y.O. and Z.K.

Phenotype collection: A.A.H., A.J.G., A.v.E., B.M.P., E.O., G.C., G.G., G.K.G., G.W., H. Snieder, I.J.D., I.K., I. Persico, J.C., J.F.W., J.V., L. Frogheri, M. Ciullo, M. Caulfield, M.G.D., M.G.P., M.J.B., M. Kähönen, M. Kubo, M.L., M. Pirastu, M.V., N.J.S., O.D., O.M.W., O.P., P. Sharma, P.B.M., P.K., P. Mudgal, P.P.P., P.V., S. Schipf, S.H.W., S.M.F., S.T., S.U., T. Zemunik and V.S.

Genotyping: A.A.H., A. Tenesa, A. Teumer, C. Hayward, D.I.C., E.L., F.E., G.C., G.D., G.W.M., I. Persico, J.F.W., M. Ciullo, M. Caulfield, M.E.K., M.G.D., M.G.P., M. Kubo, M.L., M. Putku, M.W., N.J.S., N. Klopp, O.R., P.B.M., P.D., P.M.R., P.P.P., P.v.d.H., R.J.S., S.M.F., T.E., T.L., T. Zeller and T. Zemunik.

Statistical methods and analysis: A. Tenesa, A. Tin, A. Köttgen, A. Teumer, A. Demirkan, C. Hayward, C. Hundertmark, C.G., C. Schurmann, D.C., D.I.C., D.R., E.A., E.G.H., F.M., F.T., G.A.T., G.K.G., G.L., G.M., G.P., I.M.L., I. Prokopenko, J.H., J.K., L.M.L., L.M.R., L.P., M.A.N., M. Steri, M. Bochud, M.E.K., M.F., M. Kähönen, M. Stumvoll, M. Putku, N.P., O.D., P. Mudgal, P.N., P.v.d.H., R.M.P., R.P.S.M., S.C., S.H.W., S. Sanna, T.E., T.H., T.L., V.V., W.H.L.K., X. Li, Y.O. and Z.K.

Interpretation of results: A. Tenesa, A. Tin, A. Köttgen, A.L.G., A. Teumer, B.M.P., C.G., D.R., E.A., G.W.M., H. Campbell, H. Snieder, J.K., M. Ciullo, M.A.N., M. Bochud, M. Caulfield, O.M.W., P.v.d.H., R.M.P., S.H.W., T.H., T.L., Toshihiro Tanaka, V.V., W.H.L.K., Y.O. and Z.K.

Manuscript review: A.A.H., A.B.S., A. Tenesa, A. Dehghan, A.D.J., A. Tin, A. Grotevendt, A. Goel, A.G.U., A.H., A.I., A. Jula, A. Köttgen, A.L., A.L.G., A. Kraja, A.M., A. Döring, A. Tönjes, A.P., A.R.S., A.S., A. Johansson, A. Teumer, A.V.S., B.B., B.H.R.W., B.M.P., B.O.B., B.R.W., B.W.P., C. Hundertmark, C. Hengstenberg, C. Sala, C.L., C.M., C.M.v.D., C.O., C.M.O., C.P.N., C. Schurmann, C.S.F., D.I.C., D.R., D.R.J., D.S.S., D.T., E.B., E.G.H., E. Theodoratou, F.C., F.E., F.R., F.T., G.A.T., G.C., G.G., G.N., G.W.M., H. Campbell, H. Choi, H. Schmidt, H.L.H., H.O., H. Snieder, H.V., H.W., I.B.B., I.K., I.M.L., I.M.N., I. Prokopenko, I.R., J.A., J.B.W., J.C., J.C.C., J.C.M.W., J.E.M., J.F.M., J.F.P., J.F.W., J.H.S., J.H.Z., J.I.R., J.K., J.S., J.S.K., J.V., K.B., K.L., K.S., K.T.K., L.J.L., L. Ferrucci, L.Y., M. Bruinenberg, M.A.N., M. Bochud, M. Caulfield, M. Ciullo, M.F., M.F.F., M.G.D., M.I., M. Burnier, M. Stumvoll, M. Kähönen, M. Kirin, M.M., M.N., M. Perola, M. Struchalin, M. Schallert, M.W., N.B.-N., N.G.M., N.J.W., N. Kamatani, N.M.P.-H., N.S., O.D., O.P., O.R., P. Sharma, P.F., P.K., P. McArdle, P.P.P., P. Salo, P.S.W., P.V., P.v.d.H., Q.Y., Q.Z., R. Schmidt, R.J.F.L., R.J.S., R.N., R.P.S., R. Sorice, S.B., S.H.W., S.J.L.B., S.K., S.L., S.R., S. Sanna, S.-Y.S., T.B.H., T.D.S., T.H., T.L., Toshiko Tanaka, T. Zemunik, U.G., V.G., V.L., V.V., W.H.L.K., W.H.v.G., W.M., W.Z., X. Liu, Y.N., Y.O. and Z.K.

Analysis group: A. Köttgen, A. Teumer, C.G., C. Hundertmark, C.S.F., D.R., E.A., G.P., J.K., Q.Y., T.H., Toshiko Tanaka, V.V. and W.H.L.K.

Writing group: A. Köttgen, A. Teumer, C.G., C.M.O., C.S.F., E.A., J.K., M. Bochud, M. Caulfield, M. Ciullo and V.V.

Correspondence to Anna Köttgen or Veronique Vitart or Murielle Bochud or Christian Gieger.

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Competing interests

The authors declare no competing financial interests.

Additional information

A list of contributing members appears in the Supplementary Note.

A list of contributing members appears in the Supplementary Note.

A list of contributing members appears in the Supplementary Note.

A list of contributing members appears in the Supplementary Note.

A list of contributing members appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9, Supplementary Tables 1–3, 5, 7–9, 11, 14, 16 and 18 and Supplementary Note (PDF 4438 kb)

Supplementary Table 4

All SNPs Associated with Serum Urate at p<5*10-8 (XLSX 247 kb)

Supplementary Table 6

Separate Results from Discovery, Replication and Combined Analyses for SNP-Urate Associations (XLSX 26 kb)

Supplementary Table 10

All SNPs Associated with Gout at p<1*10-6 (XLSX 53 kb)

Supplementary Table 12

Overall and Sex-Specific Association between SNPs and Fractional Excretion of Uric Acid (FEUA) (XLSX 23 kb)

Supplementary Table 13

Associations of Urate-Associated SNPs in African Americans and Individuals of Indian and Japanese Ancestry (XLSX 20 kb)

Supplementary Table 15

Association of Replicated Urate-Associated SNPs with Related Phenotypes (XLSX 22 kb)

Supplementary Table 17

Functional Network Associations Underlying Supplementary Figure 8 and Supplementary Figure 9 (XLSX 23 kb)

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Köttgen, A., Albrecht, E., Teumer, A. et al. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet 45, 145–154 (2013) doi:10.1038/ng.2500

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