Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
PublisherNature Publishing Group
MetadataShow full item record
AbstractElevated 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. Copyright 2019, The Author(s).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85074209366&doi=10.1038%2fs41588-019-0504-x&partnerID=40&md5=60891509192ac99ec8d25b79b43480ec; http://hdl.handle.net/10713/11382
- A non-coding genetic variant maximally associated with serum urate levels is functionally linked to HNF4A-dependent PDZK1 expression.
- Authors: Ketharnathan S, Leask M, Boocock J, Phipps-Green AJ, Antony J, O'Sullivan JM, Merriman TR, Horsfield JA
- Issue date: 2018 Nov 15
- Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout.
- Authors: Woodward OM, Köttgen A, Coresh J, Boerwinkle E, Guggino WB, Köttgen M
- Issue date: 2009 Jun 23
- Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.
- Authors: Yang Q, Köttgen A, Dehghan A, Smith AV, Glazer NL, Chen MH, Chasman DI, Aspelund T, Eiriksdottir G, Harris TB, Launer L, Nalls M, Hernandez D, Arking DE, Boerwinkle E, Grove ML, Li M, Linda Kao WH, Chonchol M, Haritunians T, Li G, Lumley T, Psaty BM, Shlipak M, Hwang SJ, Larson MG, O'Donnell CJ, Upadhyay A, van Duijn CM, Hofman A, Rivadeneira F, Stricker B, Uitterlinden AG, Paré G, Parker AN, Ridker PM, Siscovick DS, Gudnason V, Witteman JC, Fox CS, Coresh J
- Issue date: 2010 Dec
- Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.
- Authors: Tin A, Woodward OM, Kao WH, Liu CT, Lu X, Nalls MA, Shriner D, Semmo M, Akylbekova EL, Wyatt SB, Hwang SJ, Yang Q, Zonderman AB, Adeyemo AA, Palmer C, Meng Y, Reilly M, Shlipak MG, Siscovick D, Evans MK, Rotimi CN, Flessner MF, Köttgen M, Cupples LA, Fox CS, Köttgen A, CARe and CHARGE Consortia.
- Issue date: 2011 Oct 15
- An update on the genetic architecture of hyperuricemia and gout.
- Authors: Merriman TR
- Issue date: 2015 Apr 10