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

Adrienne Tin; Pascal Schlosser; The Estonian Biobank Research Team; The Genetics of DNA Methylation Consortium; 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; Sanaz Sedaghat; Joyce B.J. van Meurs; Wei Zhao; 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
, The Estonian Biobank Research Team
, The Genetics of DNA Methylation Consortium
, 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, Sanaz Sedaghat, Joyce B.J. van Meurs, Wei Zhao, Alexander Teumer, Anna Köttgen

^*Corresponding author for this work

Genetics of DNA methylation Consortium
University of Mississippi Medical Center
Johns Hopkins Bloomberg School of Public Health
University of Freiburg Medical Center
German Research Center for Environmental Health
Technical University of Munich
University Medical Centre Groningen
The Framingham Heart Study
National Heart, Lung, and Blood Institute (Mass.)
UPenn School of Medicine
Broad Institute of MIT and Harvard
Massachusetts General Hospital
University of Greifswald
University of Bristol
Bristol Medical School
University of Maryland School of Medicine
National Human Genome Research Institute (NHGRI)
Amsterdam Public Health Research Institute
Karolinska Institutet
Dalarna University
German Center for Neurodegenerative Diseases
University of Bonn
Mailman School of Public Health
University of Lausanne
German Cancer Research Center
Heidelberg University
University of Texas Health Science Center at Houston
University of Fribourg
University of Edinburgh
Friedrich-Alexander University Erlangen-Nürnberg
Charité – Universitätsmedizin Berlin
Munich Heart Alliance; partner site Munich
University of Washington School of Medicine
University of Washington
Johns Hopkins School of Medicine
Feinberg School of Medicine
David Geffen School of Medicine
University of California at Los Angeles
Partner Site Greifswald
University Medicine Greifswald
Medical University of Białystok
University of Michigan, Ann Arbor
University of Minnesota
Heinrich Heine University Düsseldorf
University of Amsterdam
Peking University
Columbia University
German Centre for Neurodegenerative Diseases (DZNE)
University of Freiburg

Research output: Contribution to journal › Article › Academic › peer-review

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42 Downloads (Pure)

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.

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

Bibliographical note

Funding Information:
J. Ärnlöv has served on advisory boards for AstraZeneca and Boehringer Ingelheim, and has received lecturing fees from AstraZeneca and Novartis, all unrelated to the present project. J. Coresh has grants from NIH and is a consultant to healthy.io. J. S. Floyd has consulted for Shionogi Inc. C. Herder reports personal fees from Sanofi and Lilly and grant support from Sanofi outside the submitted work. M. E. Kleber is employed with SYNLAB Holding Deutschland GmbH. O. Woodward has grants from AstraZeneca outside the submitted work. W. Koenig reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daichii-Sankyo, Genentech, Novo Nordisk, Omeicos, Esperion, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb and grants and non-financial support from Abbott, Roche Diagnostics, Beck-mann, and Singulex outside the submitted work. S. Lorkowski reports grants and personal fees from Akcea Therapeutics Germany, and personal fees from amedes, AMGEN, Berlin-Chemie, Boehringer Ingelheim Pharma, Daiichi Sankyo, Lilly Deutschland, MSD Sharp & Dohme, Novo Nordisk Pharma, Roche Pharma, Sanofi-Aventis, Synlab Holding Deutschland, Unilever, and Upfield, all outside the submitted work. R. E. Marioni has received payment from Illumina for presentations. W. März reports grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH, grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, other from Synlab Holding Deutschland GmbH, all outside the submitted work. B. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J. Sundström reports ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer, and Astra-Zeneca, outside the submitted work. B. Kühnel is currently an employee of Regeneron Genetics Center. All other authors have nothing to declare.

Publisher Copyright:
© 2021, The Author(s).

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Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locusFinal published version, 3.45 MBLicence: CC BY

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Tin, A., Schlosser, P., The Estonian Biobank Research Team, The Genetics of DNA Methylation Consortium, 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., ... 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{4e8c05961c6843729d37abbcfff6d7bd,

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{\textendash}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.",

author = "Adrienne Tin and Pascal Schlosser and \{The Estonian Biobank Research Team\} and \{The Genetics of DNA Methylation Consortium\} 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 Eckardt, \{Kai Uwe\} 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 Sanaz Sedaghat and \{van Meurs\}, \{Joyce B.J.\} and Wei Zhao and Alexander Teumer and Anna K{\"o}ttgen",

note = "Funding Information: J. {\"A}rnl{\"o}v has served on advisory boards for AstraZeneca and Boehringer Ingelheim, and has received lecturing fees from AstraZeneca and Novartis, all unrelated to the present project. J. Coresh has grants from NIH and is a consultant to healthy.io. J. S. Floyd has consulted for Shionogi Inc. C. Herder reports personal fees from Sanofi and Lilly and grant support from Sanofi outside the submitted work. M. E. Kleber is employed with SYNLAB Holding Deutschland GmbH. O. Woodward has grants from AstraZeneca outside the submitted work. W. Koenig reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daichii-Sankyo, Genentech, Novo Nordisk, Omeicos, Esperion, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb and grants and non-financial support from Abbott, Roche Diagnostics, Beck-mann, and Singulex outside the submitted work. S. Lorkowski reports grants and personal fees from Akcea Therapeutics Germany, and personal fees from amedes, AMGEN, Berlin-Chemie, Boehringer Ingelheim Pharma, Daiichi Sankyo, Lilly Deutschland, MSD Sharp \& Dohme, Novo Nordisk Pharma, Roche Pharma, Sanofi-Aventis, Synlab Holding Deutschland, Unilever, and Upfield, all outside the submitted work. R. E. Marioni has received payment from Illumina for presentations. W. M{\"a}rz reports grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH, grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, other from Synlab Holding Deutschland GmbH, all outside the submitted work. B. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson \& Johnson. J. Sundstr{\"o}m reports ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer, and Astra-Zeneca, outside the submitted work. B. K{\"u}hnel is currently an employee of Regeneron Genetics Center. All other authors have nothing to declare. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

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

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Tin, A, Schlosser, P, The Estonian Biobank Research Team, The Genetics of DNA Methylation Consortium, 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, KU, 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, Sedaghat, S, van Meurs, JBJ, Zhao, W, 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 - The Estonian Biobank Research Team

AU - The Genetics of DNA Methylation Consortium

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 - Sedaghat, Sanaz

AU - van Meurs, Joyce B.J.

AU - Zhao, Wei

AU - Teumer, Alexander

AU - Köttgen, Anna

N1 - Funding Information: J. Ärnlöv has served on advisory boards for AstraZeneca and Boehringer Ingelheim, and has received lecturing fees from AstraZeneca and Novartis, all unrelated to the present project. J. Coresh has grants from NIH and is a consultant to healthy.io. J. S. Floyd has consulted for Shionogi Inc. C. Herder reports personal fees from Sanofi and Lilly and grant support from Sanofi outside the submitted work. M. E. Kleber is employed with SYNLAB Holding Deutschland GmbH. O. Woodward has grants from AstraZeneca outside the submitted work. W. Koenig reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daichii-Sankyo, Genentech, Novo Nordisk, Omeicos, Esperion, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb and grants and non-financial support from Abbott, Roche Diagnostics, Beck-mann, and Singulex outside the submitted work. S. Lorkowski reports grants and personal fees from Akcea Therapeutics Germany, and personal fees from amedes, AMGEN, Berlin-Chemie, Boehringer Ingelheim Pharma, Daiichi Sankyo, Lilly Deutschland, MSD Sharp & Dohme, Novo Nordisk Pharma, Roche Pharma, Sanofi-Aventis, Synlab Holding Deutschland, Unilever, and Upfield, all outside the submitted work. R. E. Marioni has received payment from Illumina for presentations. W. März reports grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH, grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, other from Synlab Holding Deutschland GmbH, all outside the submitted work. B. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J. Sundström reports ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer, and Astra-Zeneca, outside the submitted work. B. Kühnel is currently an employee of Regeneron Genetics Center. All other authors have nothing to declare. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

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.

UR - https://www.scopus.com/pages/publications/85121013020

U2 - 10.1038/s41467-021-27198-4

DO - 10.1038/s41467-021-27198-4

M3 - Article

C2 - 34887389

AN - SCOPUS:85121013020

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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