Large-scale cross-ancestry genome-wide meta-analysis of serum urate

Nat Commun. 2024 Apr 24;15(1):3441. doi: 10.1038/s41467-024-47805-4.

Abstract

Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Gout / blood
  • Gout / genetics
  • Heart Failure / blood
  • Heart Failure / genetics
  • Humans
  • Hypertension / blood
  • Hypertension / genetics
  • Hyperuricemia* / blood
  • Hyperuricemia* / genetics
  • Mendelian Randomization Analysis
  • Multifactorial Inheritance
  • Polymorphism, Single Nucleotide
  • Transcriptome
  • Uric Acid* / blood

Substances

  • DNA-Binding Proteins
  • Uric Acid