TY - JOUR
T1 - Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
AU - German Chronic Kidney Disease Study
AU - Lifelines Cohort Study
AU - V. A. Million Veteran Program
AU - Tin, Adrienne
AU - Marten, Jonathan
AU - Halperin Kuhns, Victoria L.
AU - Li, Yong
AU - Wuttke, Matthias
AU - Kirsten, Holger
AU - Sieber, Karsten B.
AU - Qiu, Chengxiang
AU - Gorski, Mathias
AU - Yu, Zhi
AU - Giri, Ayush
AU - Sveinbjornsson, Gardar
AU - Li, Man
AU - Chu, Audrey Y.
AU - Hoppmann, Anselm
AU - O’Connor, Luke J.
AU - Prins, Bram
AU - Nutile, Teresa
AU - Noce, Damia
AU - Akiyama, Masato
AU - Cocca, Massimiliano
AU - Ghasemi, Sahar
AU - van der Most, Peter J.
AU - Horn, Katrin
AU - Xu, Yizhe
AU - Fuchsberger, Christian
AU - Sedaghat, Sanaz
AU - Afaq, Saima
AU - Amin, Najaf
AU - Ärnlöv, Johan
AU - Bakker, Stephan J.L.
AU - Bansal, Nisha
AU - Baptista, Daniela
AU - Bergmann, Sven
AU - Biggs, Mary L.
AU - Biino, Ginevra
AU - Boerwinkle, Eric
AU - Bottinger, Erwin P.
AU - Boutin, Thibaud S.
AU - Brumat, Marco
AU - Burkhardt, Ralph
AU - Campana, Eric
AU - Campbell, Archie
AU - Campbell, Harry
AU - Carroll, Robert J.
AU - Catamo, Eulalia
AU - Chambers, John C.
AU - Ciullo, Marina
AU - Concas, Maria Pina
AU - Coresh, Josef
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
AB - Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
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U2 - 10.1038/s41588-019-0504-x
DO - 10.1038/s41588-019-0504-x
M3 - Article
C2 - 31578528
AN - SCOPUS:85074209366
SN - 1061-4036
VL - 51
SP - 1459
EP - 1474
JO - Nature Genetics
JF - Nature Genetics
IS - 10
ER -