Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

German Chronic Kidney Disease Study, Daniela Ruggiero

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1459-1474
Number of pages16
JournalNature Genetics
Volume51
Issue number10
DOIs
Publication statusPublished - Oct 2019

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Keywords

  • ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
  • Cardiovascular Diseases/blood
  • Cohort Studies
  • Genetic Loci
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Gout/blood
  • Hepatocyte Nuclear Factor 1-alpha/genetics
  • Hepatocyte Nuclear Factor 4/genetics
  • Humans
  • Kidney/metabolism
  • Liver/metabolism
  • Metabolic Diseases/blood
  • Neoplasm Proteins/genetics
  • Organ Specificity
  • Polymorphism, Single Nucleotide
  • Signal Transduction
  • Uric Acid/blood

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