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.

5th Department of Medicine Medical Faculty Mannheim University of Heidelberg Mannheim Germany

Bio4Dreams Milano Italy

Biomedical Laboratory Research and Development Tennessee Valley Healthcare System Vanderbilt University Nashville TN USA

Cardiology Geneva University Hospitals Geneva Switzerland

Cardiovascular Health Research Unit Department of Medicine Department of Epidemiology Department of Health Service University of Washington Seattle WA USA

Cardiovascular Health Research Unit Department of Medicine University of Washington Seattle WA USA

Center for Cardiovascular Prevention 1st Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic

Center for Primary Care and Public Health University of Lausanne Lausanne Switzerland

Centre de Recherche du CHUM Montreal Quebec Canada

Centre for Cognitive Ageing and Cognitive Epidemiology University of Edinburgh Edinburgh UK

Centre for Genomic and Experimental Medicine Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh UK

Centre for Global Health Research Usher Institute of Population Health Sciences and Informatics University of Edinburgh Edinburgh UK

Centre for Pediatric Research University of Leipzig Leipzig Germany

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Centre for Population Health Sciences Usher Institute of Population Health Sciences and Informatics University of Edinburgh Edinburgh UK

Chair of Genetic Epidemiology IBE Faculty of Medicine LMU Munich Munich Germany

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A genome-wide association analysis reveals new pathogenic pathways in gout

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients