Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus
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 epigen...
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| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Online Access: | https://hdl.handle.net/10356/163229 |
| _version_ | 1811696857644007424 |
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| author | Tin, Adrienne Schlosser, Pascal Matias-Garcia, Pamela R. Thio, Chris H. L. Joehanes, Roby Liu, Hongbo Yu, Zhi Weihs, Antoine Hoppmann, Anselm Grundner-Culemann, Franziska Min, Josine L. Kuhns, Victoria L. Halperin Adeyemo, Adebowale A. Agyemang, Charles Ärnlöv, Johan Aziz, Nasir A. Baccarelli, Andrea Bochud, Murielle Brenner, Hermann Bressler, Jan Breteler, Monique M. B. Carmeli, Cristian Chaker, Layal Coresh, Josef Corre, Tanguy Correa, Adolfo Cox, Simon R. Delgado, Graciela E. Eckardt, Kai-Uwe Ekici, Arif B. Endlich, Karlhans Floyd, James S. Fraszczyk, Eliza Gao, Xu Gào, Xīn Gelber, Allan C. Ghanbari, Mohsen Ghasemi, Sahar Gieger, Christian Greenland, Philip Grove, Megan L. Harris, Sarah E. Hemani, Gibran Henneman, Peter Herder, Christian Horvath, Steve Hou, Lifang Hurme, Mikko A. Hwang, Shih-Jen Kardia, Sharon L. R. Kasela, Silva Kleber, Marcus E. Koenig, Wolfgang Kooner, Jaspal S. Kronenberg, Florian Kühnel, Brigitte Ladd-Acosta, Christine Lehtimäki, Terho Lind, Lars Liu, Dan Lloyd-Jones, Donald M. Lorkowski, Stefan Lu, Ake T. Marioni, Riccardo E. März, Winfried McCartney, Daniel L. Meeks, Karlijn A. C. Milani, Lili Mishra, Pashupati P. Nauck, Matthias Nowak, Christoph Peters, Annette Prokisch, Holger Psaty, Bruce M. Raitakari, Olli T. Ratliff, Scott M. Reiner, Alex P. Schöttker, Ben Schwartz, Joel Sedaghat, Sanaz Smith, Jennifer A. Sotoodehnia, Nona Stocker, Hannah R. Stringhini, Silvia Sundström, Johan Swenson, Brenton R. van Meurs, Joyce B. J. van Vliet-Ostaptchouk, Jana V. Venema, Andrea Völker, Uwe Winkelmann, Juliane Wolffenbuttel, Bruce H. R. Zhao, Wei Zheng, Yinan Milani, Lili Esko, Tõnu Metspalu, Andres Mägi, Reedik Nelis, Mari Min, Josine L. Hemani, Gibran Loh, Marie Snieder, Harold Waldenberger, Melanie Levy, Daniel Akilesh, Shreeram Woodward, Owen M. Susztak, Katalin Teumer, Alexander Köttgen, Anna |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Tin, Adrienne Schlosser, Pascal Matias-Garcia, Pamela R. Thio, Chris H. L. Joehanes, Roby Liu, Hongbo Yu, Zhi Weihs, Antoine Hoppmann, Anselm Grundner-Culemann, Franziska Min, Josine L. Kuhns, Victoria L. Halperin Adeyemo, Adebowale A. Agyemang, Charles Ärnlöv, Johan Aziz, Nasir A. Baccarelli, Andrea Bochud, Murielle Brenner, Hermann Bressler, Jan Breteler, Monique M. B. Carmeli, Cristian Chaker, Layal Coresh, Josef Corre, Tanguy Correa, Adolfo Cox, Simon R. Delgado, Graciela E. Eckardt, Kai-Uwe Ekici, Arif B. Endlich, Karlhans Floyd, James S. Fraszczyk, Eliza Gao, Xu Gào, Xīn Gelber, Allan C. Ghanbari, Mohsen Ghasemi, Sahar Gieger, Christian Greenland, Philip Grove, Megan L. Harris, Sarah E. Hemani, Gibran Henneman, Peter Herder, Christian Horvath, Steve Hou, Lifang Hurme, Mikko A. Hwang, Shih-Jen Kardia, Sharon L. R. Kasela, Silva Kleber, Marcus E. Koenig, Wolfgang Kooner, Jaspal S. Kronenberg, Florian Kühnel, Brigitte Ladd-Acosta, Christine Lehtimäki, Terho Lind, Lars Liu, Dan Lloyd-Jones, Donald M. Lorkowski, Stefan Lu, Ake T. Marioni, Riccardo E. März, Winfried McCartney, Daniel L. Meeks, Karlijn A. C. Milani, Lili Mishra, Pashupati P. Nauck, Matthias Nowak, Christoph Peters, Annette Prokisch, Holger Psaty, Bruce M. Raitakari, Olli T. Ratliff, Scott M. Reiner, Alex P. Schöttker, Ben Schwartz, Joel Sedaghat, Sanaz Smith, Jennifer A. Sotoodehnia, Nona Stocker, Hannah R. Stringhini, Silvia Sundström, Johan Swenson, Brenton R. van Meurs, Joyce B. J. van Vliet-Ostaptchouk, Jana V. Venema, Andrea Völker, Uwe Winkelmann, Juliane Wolffenbuttel, Bruce H. R. Zhao, Wei Zheng, Yinan Milani, Lili Esko, Tõnu Metspalu, Andres Mägi, Reedik Nelis, Mari Min, Josine L. Hemani, Gibran Loh, Marie Snieder, Harold Waldenberger, Melanie Levy, Daniel Akilesh, Shreeram Woodward, Owen M. Susztak, Katalin Teumer, Alexander Köttgen, Anna |
| author_sort | Tin, Adrienne |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T07:46:02Z |
| format | Journal Article |
| id | ntu-10356/163229 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:46:02Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1632292023-03-05T16:52:35Z Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus Tin, Adrienne Schlosser, Pascal Matias-Garcia, Pamela R. Thio, Chris H. L. Joehanes, Roby Liu, Hongbo Yu, Zhi Weihs, Antoine Hoppmann, Anselm Grundner-Culemann, Franziska Min, Josine L. Kuhns, Victoria L. Halperin Adeyemo, Adebowale A. Agyemang, Charles Ärnlöv, Johan Aziz, Nasir A. Baccarelli, Andrea Bochud, Murielle Brenner, Hermann Bressler, Jan Breteler, Monique M. B. Carmeli, Cristian Chaker, Layal Coresh, Josef Corre, Tanguy Correa, Adolfo Cox, Simon R. Delgado, Graciela E. Eckardt, Kai-Uwe Ekici, Arif B. Endlich, Karlhans Floyd, James S. Fraszczyk, Eliza Gao, Xu Gào, Xīn Gelber, Allan C. Ghanbari, Mohsen Ghasemi, Sahar Gieger, Christian Greenland, Philip Grove, Megan L. Harris, Sarah E. Hemani, Gibran Henneman, Peter Herder, Christian Horvath, Steve Hou, Lifang Hurme, Mikko A. Hwang, Shih-Jen Kardia, Sharon L. R. Kasela, Silva Kleber, Marcus E. Koenig, Wolfgang Kooner, Jaspal S. Kronenberg, Florian Kühnel, Brigitte Ladd-Acosta, Christine Lehtimäki, Terho Lind, Lars Liu, Dan Lloyd-Jones, Donald M. Lorkowski, Stefan Lu, Ake T. Marioni, Riccardo E. März, Winfried McCartney, Daniel L. Meeks, Karlijn A. C. Milani, Lili Mishra, Pashupati P. Nauck, Matthias Nowak, Christoph Peters, Annette Prokisch, Holger Psaty, Bruce M. Raitakari, Olli T. Ratliff, Scott M. Reiner, Alex P. Schöttker, Ben Schwartz, Joel Sedaghat, Sanaz Smith, Jennifer A. Sotoodehnia, Nona Stocker, Hannah R. Stringhini, Silvia Sundström, Johan Swenson, Brenton R. van Meurs, Joyce B. J. van Vliet-Ostaptchouk, Jana V. Venema, Andrea Völker, Uwe Winkelmann, Juliane Wolffenbuttel, Bruce H. R. Zhao, Wei Zheng, Yinan Milani, Lili Esko, Tõnu Metspalu, Andres Mägi, Reedik Nelis, Mari Min, Josine L. Hemani, Gibran Loh, Marie Snieder, Harold Waldenberger, Melanie Levy, Daniel Akilesh, Shreeram Woodward, Owen M. Susztak, Katalin Teumer, Alexander Köttgen, Anna Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Phosphoglycerate Dehydrogenase Cardiometabolic Risk Factor 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. Ministry of Health (MOH) National Medical Research Council (NMRC) Published version Study-specific acknowledgements and funding sources are listed as Supplementary Note 1. Open Access funding enabled and organized by Projekt DEAL. 2022-11-29T04:20:41Z 2022-11-29T04:20:41Z 2021 Journal Article 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), 7173-. https://dx.doi.org/10.1038/s41467-021-27198-4 2041-1723 https://hdl.handle.net/10356/163229 10.1038/s41467-021-27198-4 34887389 2-s2.0-85121013020 1 12 7173 en NMRC/STaR/0028/2017 Nature Communications © The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. application/pdf application/pdf |
| spellingShingle | Science::Medicine Phosphoglycerate Dehydrogenase Cardiometabolic Risk Factor Tin, Adrienne Schlosser, Pascal Matias-Garcia, Pamela R. Thio, Chris H. L. Joehanes, Roby Liu, Hongbo Yu, Zhi Weihs, Antoine Hoppmann, Anselm Grundner-Culemann, Franziska Min, Josine L. Kuhns, Victoria L. Halperin Adeyemo, Adebowale A. Agyemang, Charles Ärnlöv, Johan Aziz, Nasir A. Baccarelli, Andrea Bochud, Murielle Brenner, Hermann Bressler, Jan Breteler, Monique M. B. Carmeli, Cristian Chaker, Layal Coresh, Josef Corre, Tanguy Correa, Adolfo Cox, Simon R. Delgado, Graciela E. Eckardt, Kai-Uwe Ekici, Arif B. Endlich, Karlhans Floyd, James S. Fraszczyk, Eliza Gao, Xu Gào, Xīn Gelber, Allan C. Ghanbari, Mohsen Ghasemi, Sahar Gieger, Christian Greenland, Philip Grove, Megan L. Harris, Sarah E. Hemani, Gibran Henneman, Peter Herder, Christian Horvath, Steve Hou, Lifang Hurme, Mikko A. Hwang, Shih-Jen Kardia, Sharon L. R. Kasela, Silva Kleber, Marcus E. Koenig, Wolfgang Kooner, Jaspal S. Kronenberg, Florian Kühnel, Brigitte Ladd-Acosta, Christine Lehtimäki, Terho Lind, Lars Liu, Dan Lloyd-Jones, Donald M. Lorkowski, Stefan Lu, Ake T. Marioni, Riccardo E. März, Winfried McCartney, Daniel L. Meeks, Karlijn A. C. Milani, Lili Mishra, Pashupati P. Nauck, Matthias Nowak, Christoph Peters, Annette Prokisch, Holger Psaty, Bruce M. Raitakari, Olli T. Ratliff, Scott M. Reiner, Alex P. Schöttker, Ben Schwartz, Joel Sedaghat, Sanaz Smith, Jennifer A. Sotoodehnia, Nona Stocker, Hannah R. Stringhini, Silvia Sundström, Johan Swenson, Brenton R. van Meurs, Joyce B. J. van Vliet-Ostaptchouk, Jana V. Venema, Andrea Völker, Uwe Winkelmann, Juliane Wolffenbuttel, Bruce H. R. Zhao, Wei Zheng, Yinan Milani, Lili Esko, Tõnu Metspalu, Andres Mägi, Reedik Nelis, Mari Min, Josine L. Hemani, Gibran Loh, Marie Snieder, Harold Waldenberger, Melanie Levy, Daniel Akilesh, Shreeram Woodward, Owen M. Susztak, Katalin Teumer, Alexander Köttgen, Anna Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus |
| title | Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus |
| title_full | Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus |
| title_fullStr | Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus |
| title_full_unstemmed | Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus |
| title_short | Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus |
| title_sort | epigenome wide association study of serum urate reveals insights into urate co regulation and the slc2a9 locus |
| topic | Science::Medicine Phosphoglycerate Dehydrogenase Cardiometabolic Risk Factor |
| url | https://hdl.handle.net/10356/163229 |
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epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT eskotonu epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT metspaluandres epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT magireedik epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT nelismari epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT minjosinel epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT hemanigibran epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT lohmarie epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT sniederharold epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT waldenbergermelanie epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT levydaniel epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT akileshshreeram epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT woodwardowenm epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT susztakkatalin epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT teumeralexander epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus AT kottgenanna epigenomewideassociationstudyofserumuraterevealsinsightsintouratecoregulationandtheslc2a9locus |