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dc.contributor.authorHalperin, Kuhns, V.L.
dc.contributor.authorLewis, R.M.
dc.contributor.authorRyan, K.A.
dc.contributor.authorO'Connell, J.R.
dc.contributor.authorWoodward, O.M.
dc.date.accessioned2019-11-06T15:55:50Z
dc.date.available2019-11-06T15:55:50Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85074209366&doi=10.1038%2fs41588-019-0504-x&partnerID=40&md5=60891509192ac99ec8d25b79b43480ec
dc.identifier.urihttp://hdl.handle.net/10713/11382
dc.description.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).en_US
dc.description.sponsorshipen_US
dc.description.urihttps://doi.org/10.1038/s41588-019-0504-xen_US
dc.language.isoen_USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofNature Genetics
dc.subjectcardiometabolic traitsen_US
dc.subject.meshUric Aciden_US
dc.subject.meshGenome-Wide Association Studyen_US
dc.subject.meshGene Expressionen_US
dc.subject.meshKidneyen_US
dc.subject.meshLiveren_US
dc.subject.meshGouten_US
dc.titleTarget genes, variants, tissues and transcriptional pathways influencing human serum urate levelsen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41588-019-0504-x
dc.identifier.pmid31578528


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