Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus
Authors: 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 ,   The Estonian Biobank Research Team,   The Genetics of DNA Methylation Consortium, Loh Marie , Snieder Harold , Waldenberger Melanie , Levy Daniel , Akilesh Shreeram , Woodward Owen M. , Susztak Katalin , Teumer Alexander , Köttgen Anna 
Published: December 2021

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.