Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

Adrienne Tin; Pascal Schlosser; Pamela R. Matias-garcia; Chris H. L. Thio; Roby Joehanes; Hongbo Liu; Zhi Yu; Antoine Weihs; Anselm Hoppmann; Franziska Grundner-culemann; Josine L. Min; Victoria L. Halperin Kuhns; Adebowale A. Adeyemo; Charles Agyemang; Johan Ärnlöv; Nasir A. Aziz; Andrea Baccarelli; Murielle Bochud; Hermann Brenner; Jan Bressler; Monique M. B. Breteler; Cristian Carmeli; Layal Chaker; Josef Coresh; Tanguy Corre; Adolfo Correa; Simon R. Cox; Graciela E. Delgado; Kai-uwe Eckardt; Arif B. Ekici; Karlhans Endlich; James S. Floyd; Eliza Fraszczyk; Xu Gao; Xīn Gào; Allan C. Gelber; Mohsen Ghanbari; Sahar Ghasemi; Christian Gieger; Philip Greenland; Megan L. Grove; Sarah E. Harris; Gibran Hemani; Peter Henneman; Christian Herder; Steve Horvath; Lifang Hou; Mikko A. Hurme; Shih-jen Hwang; Sharon L. R. Kardia; Silva Kasela; Marcus E. Kleber; Wolfgang Koenig; Jaspal S. Kooner; Florian Kronenberg; Brigitte Kühnel; Christine Ladd-acosta; Terho Lehtimäki; Lars Lind; Dan Liu; Donald M. Lloyd-jones; Stefan Lorkowski; Ake T. Lu; Riccardo E. Marioni; Winfried März; Daniel L. Mccartney; Karlijn A. C. Meeks; Lili Milani; Pashupati P. Mishra; Matthias Nauck; Christoph Nowak; Annette Peters; Holger Prokisch; Bruce M. Psaty; Olli T. Raitakari; Scott M. Ratliff; Alex P. Reiner; Ben Schöttker; Joel Schwartz; Sanaz Sedaghat; Jennifer A. Smith; Nona Sotoodehnia; Hannah R. Stocker; Silvia Stringhini; Johan Sundström; Brenton R. Swenson; Joyce B. J. Van Meurs; Jana V. Van Vliet-ostaptchouk; Andrea Venema; Uwe Völker; Juliane Winkelmann; Bruce H. R. Wolffenbuttel; Wei Zhao; Yinan Zheng; Marie Loh; Harold Snieder; Melanie Waldenberger; Daniel Levy; Shreeram Akilesh; Owen M. Woodward; Katalin Susztak; Alexander Teumer; Anna Köttgen

doi:10.1038/s41467-021-27198-4

Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

Adrienne Tin, Pascal Schlosser, Pamela R. Matias-garcia, Chris H. L. Thio, Roby Joehanes, Hongbo Liu, Zhi Yu, Antoine Weihs, Anselm Hoppmann, Franziska Grundner-culemann, Josine L. Min, Victoria L. Halperin Kuhns, Adebowale A. Adeyemo, Charles Agyemang, Johan Ärnlöv, Nasir A. Aziz, Andrea Baccarelli, Murielle Bochud, Hermann Brenner, Jan BresslerMonique M. B. Breteler, Cristian Carmeli, Layal Chaker, Josef Coresh, Tanguy Corre, Adolfo Correa, Simon R. Cox, Graciela E. Delgado, Kai-uwe Eckardt, Arif B. Ekici, Karlhans Endlich, James S. Floyd, Eliza Fraszczyk, Xu Gao, Xīn Gào, Allan C. Gelber, Mohsen Ghanbari, Sahar Ghasemi, Christian Gieger, Philip Greenland, Megan L. Grove, Sarah E. Harris, Gibran Hemani, Peter Henneman, Christian Herder, Steve Horvath, Lifang Hou, Mikko A. Hurme, Shih-jen Hwang, Sharon L. R. Kardia, Silva Kasela, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Florian Kronenberg, Brigitte Kühnel, Christine Ladd-acosta, Terho Lehtimäki, Lars Lind, Dan Liu, Donald M. Lloyd-jones, Stefan Lorkowski, Ake T. Lu, Riccardo E. Marioni, Winfried März, Daniel L. Mccartney, Karlijn A. C. Meeks, Lili Milani, Pashupati P. Mishra, Matthias Nauck, Christoph Nowak, Annette Peters, Holger Prokisch, Bruce M. Psaty, Olli T. Raitakari, Scott M. Ratliff, Alex P. Reiner, Ben Schöttker, Joel Schwartz, Sanaz Sedaghat, Jennifer A. Smith, Nona Sotoodehnia, Hannah R. Stocker, Silvia Stringhini, Johan Sundström, Brenton R. Swenson, Joyce B. J. Van Meurs, Jana V. Van Vliet-ostaptchouk, Andrea Venema, Uwe Völker, Juliane Winkelmann, Bruce H. R. Wolffenbuttel, Wei Zhao, Yinan Zheng, Marie Loh, Harold Snieder, Melanie Waldenberger, Daniel Levy, Shreeram Akilesh, Owen M. Woodward, Katalin Susztak, Alexander Teumer, Anna Köttgen

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Abstract / Description of output

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

Original language	English
Article number	7173
Journal	Nature Communications
Volume	12
Issue number	1
Early online date	9 Dec 2021
DOIs	https://doi.org/10.1038/s41467-021-27198-4
Publication status	Published - 2021

Keywords / Materials (for Non-textual outputs)

endocrine system and metabolic diseases
epidemiology
epigenomics
translational research

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Tin, A., Schlosser, P., Matias-garcia, P. R., Thio, C. H. L., Joehanes, R., Liu, H., Yu, Z., Weihs, A., Hoppmann, A., Grundner-culemann, F., Min, J. L., Kuhns, V. L. H., Adeyemo, A. A., Agyemang, C., Ärnlöv, J., Aziz, N. A., Baccarelli, A., Bochud, M., Brenner, H., ... Köttgen, A. (2021). Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. Nature Communications, 12(1), Article 7173 . https://doi.org/10.1038/s41467-021-27198-4

@article{6f33a0189d5349dd8bcb7cf168d1aa78,

title = "Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus",

abstract = "Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.",

keywords = "endocrine system and metabolic diseases, epidemiology, epigenomics, translational research",

author = "Adrienne Tin and Pascal Schlosser and Matias-garcia, {Pamela R.} and Thio, {Chris H. L.} and Roby Joehanes and Hongbo Liu and Zhi Yu and Antoine Weihs and Anselm Hoppmann and Franziska Grundner-culemann and Min, {Josine L.} and Kuhns, {Victoria L. Halperin} and Adeyemo, {Adebowale A.} and Charles Agyemang and Johan {\"A}rnl{\"o}v and Aziz, {Nasir A.} and Andrea Baccarelli and Murielle Bochud and Hermann Brenner and Jan Bressler and Breteler, {Monique M. B.} and Cristian Carmeli and Layal Chaker and Josef Coresh and Tanguy Corre and Adolfo Correa and Cox, {Simon R.} and Delgado, {Graciela E.} and Kai-uwe Eckardt and Ekici, {Arif B.} and Karlhans Endlich and Floyd, {James S.} and Eliza Fraszczyk and Xu Gao and Xīn G{\`a}o and Gelber, {Allan C.} and Mohsen Ghanbari and Sahar Ghasemi and Christian Gieger and Philip Greenland and Grove, {Megan L.} and Harris, {Sarah E.} and Gibran Hemani and Peter Henneman and Christian Herder and Steve Horvath and Lifang Hou and Hurme, {Mikko A.} and Shih-jen Hwang and Kardia, {Sharon L. R.} and Silva Kasela and Kleber, {Marcus E.} and Wolfgang Koenig and Kooner, {Jaspal S.} and Florian Kronenberg and Brigitte K{\"u}hnel and Christine Ladd-acosta and Terho Lehtim{\"a}ki and Lars Lind and Dan Liu and Lloyd-jones, {Donald M.} and Stefan Lorkowski and Lu, {Ake T.} and Marioni, {Riccardo E.} and Winfried M{\"a}rz and Mccartney, {Daniel L.} and Meeks, {Karlijn A. C.} and Lili Milani and Mishra, {Pashupati P.} and Matthias Nauck and Christoph Nowak and Annette Peters and Holger Prokisch and Psaty, {Bruce M.} and Raitakari, {Olli T.} and Ratliff, {Scott M.} and Reiner, {Alex P.} and Ben Sch{\"o}ttker and Joel Schwartz and Sanaz Sedaghat and Smith, {Jennifer A.} and Nona Sotoodehnia and Stocker, {Hannah R.} and Silvia Stringhini and Johan Sundstr{\"o}m and Swenson, {Brenton R.} and {Van Meurs}, {Joyce B. J.} and {Van Vliet-ostaptchouk}, {Jana V.} and Andrea Venema and Uwe V{\"o}lker and Juliane Winkelmann and Wolffenbuttel, {Bruce H. R.} and Wei Zhao and Yinan Zheng and Marie Loh and Harold Snieder and Melanie Waldenberger and Daniel Levy and Shreeram Akilesh and Woodward, {Owen M.} and Katalin Susztak and Alexander Teumer and Anna K{\"o}ttgen",

year = "2021",

doi = "10.1038/s41467-021-27198-4",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Tin, A, Schlosser, P, Matias-garcia, PR, Thio, CHL, Joehanes, R, Liu, H, Yu, Z, Weihs, A, Hoppmann, A, Grundner-culemann, F, Min, JL, Kuhns, VLH, Adeyemo, AA, Agyemang, C, Ärnlöv, J, Aziz, NA, Baccarelli, A, Bochud, M, Brenner, H, Bressler, J, Breteler, MMB, Carmeli, C, Chaker, L, Coresh, J, Corre, T, Correa, A, Cox, SR, Delgado, GE, Eckardt, K, Ekici, AB, Endlich, K, Floyd, JS, Fraszczyk, E, Gao, X, Gào, X, Gelber, AC, Ghanbari, M, Ghasemi, S, Gieger, C, Greenland, P, Grove, ML, Harris, SE, Hemani, G, Henneman, P, Herder, C, Horvath, S, Hou, L, Hurme, MA, Hwang, S, Kardia, SLR, Kasela, S, Kleber, ME, Koenig, W, Kooner, JS, Kronenberg, F, Kühnel, B, Ladd-acosta, C, Lehtimäki, T, Lind, L, Liu, D, Lloyd-jones, DM, Lorkowski, S, Lu, AT, Marioni, RE, März, W, Mccartney, DL, Meeks, KAC, Milani, L, Mishra, PP, Nauck, M, Nowak, C, Peters, A, Prokisch, H, Psaty, BM, Raitakari, OT, Ratliff, SM, Reiner, AP, Schöttker, B, Schwartz, J, Sedaghat, S, Smith, JA, Sotoodehnia, N, Stocker, HR, Stringhini, S, Sundström, J, Swenson, BR, Van Meurs, JBJ, Van Vliet-ostaptchouk, JV, Venema, A, Völker, U, Winkelmann, J, Wolffenbuttel, BHR, Zhao, W, Zheng, Y, Loh, M, Snieder, H, Waldenberger, M, Levy, D, Akilesh, S, Woodward, OM, Susztak, K, Teumer, A & Köttgen, A 2021, 'Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus', Nature Communications, vol. 12, no. 1, 7173 . https://doi.org/10.1038/s41467-021-27198-4

TY - JOUR

T1 - Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

AU - Tin, Adrienne

AU - Schlosser, Pascal

AU - Matias-garcia, Pamela R.

AU - Thio, Chris H. L.

AU - Joehanes, Roby

AU - Liu, Hongbo

AU - Yu, Zhi

AU - Weihs, Antoine

AU - Hoppmann, Anselm

AU - Grundner-culemann, Franziska

AU - Min, Josine L.

AU - Kuhns, Victoria L. Halperin

AU - Adeyemo, Adebowale A.

AU - Agyemang, Charles

AU - Ärnlöv, Johan

AU - Aziz, Nasir A.

AU - Baccarelli, Andrea

AU - Bochud, Murielle

AU - Brenner, Hermann

AU - Bressler, Jan

AU - Breteler, Monique M. B.

AU - Carmeli, Cristian

AU - Chaker, Layal

AU - Coresh, Josef

AU - Corre, Tanguy

AU - Correa, Adolfo

AU - Cox, Simon R.

AU - Delgado, Graciela E.

AU - Eckardt, Kai-uwe

AU - Ekici, Arif B.

AU - Endlich, Karlhans

AU - Floyd, James S.

AU - Fraszczyk, Eliza

AU - Gao, Xu

AU - Gào, Xīn

AU - Gelber, Allan C.

AU - Ghanbari, Mohsen

AU - Ghasemi, Sahar

AU - Gieger, Christian

AU - Greenland, Philip

AU - Grove, Megan L.

AU - Harris, Sarah E.

AU - Hemani, Gibran

AU - Henneman, Peter

AU - Herder, Christian

AU - Horvath, Steve

AU - Hou, Lifang

AU - Hurme, Mikko A.

AU - Hwang, Shih-jen

AU - Kardia, Sharon L. R.

AU - Kasela, Silva

AU - Kleber, Marcus E.

AU - Koenig, Wolfgang

AU - Kooner, Jaspal S.

AU - Kronenberg, Florian

AU - Kühnel, Brigitte

AU - Ladd-acosta, Christine

AU - Lehtimäki, Terho

AU - Lind, Lars

AU - Liu, Dan

AU - Lloyd-jones, Donald M.

AU - Lorkowski, Stefan

AU - Lu, Ake T.

AU - Marioni, Riccardo E.

AU - März, Winfried

AU - Mccartney, Daniel L.

AU - Meeks, Karlijn A. C.

AU - Milani, Lili

AU - Mishra, Pashupati P.

AU - Nauck, Matthias

AU - Nowak, Christoph

AU - Peters, Annette

AU - Prokisch, Holger

AU - Psaty, Bruce M.

AU - Raitakari, Olli T.

AU - Ratliff, Scott M.

AU - Reiner, Alex P.

AU - Schöttker, Ben

AU - Schwartz, Joel

AU - Sedaghat, Sanaz

AU - Smith, Jennifer A.

AU - Sotoodehnia, Nona

AU - Stocker, Hannah R.

AU - Stringhini, Silvia

AU - Sundström, Johan

AU - Swenson, Brenton R.

AU - Van Meurs, Joyce B. J.

AU - Van Vliet-ostaptchouk, Jana V.

AU - Venema, Andrea

AU - Völker, Uwe

AU - Winkelmann, Juliane

AU - Wolffenbuttel, Bruce H. R.

AU - Zhao, Wei

AU - Zheng, Yinan

AU - Loh, Marie

AU - Snieder, Harold

AU - Waldenberger, Melanie

AU - Levy, Daniel

AU - Akilesh, Shreeram

AU - Woodward, Owen M.

AU - Susztak, Katalin

AU - Teumer, Alexander

AU - Köttgen, Anna

PY - 2021

Y1 - 2021

N2 - Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

AB - Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

KW - endocrine system and metabolic diseases

KW - epidemiology

KW - epigenomics

KW - translational research

U2 - 10.1038/s41467-021-27198-4

DO - 10.1038/s41467-021-27198-4

M3 - Article

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7173

ER -

Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

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