TY - JOUR
T1 - Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus
AU - The Estonian Biobank Research Team
AU - The Genetics of DNA Methylation Consortium
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 - Sedaghat, Sanaz
N1 - 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.
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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 -