Abstract: SA-PO1007
Large-Scale Meta-Analysis in European Ancestry Identifies 114 Independent Signals for Serum Urate
Session Information
- Fluid and Electrolytes: Basic - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid and Electrolytes
- 901 Fluid and Electrolytes: Basic
Authors
- Tin, Adrienne, Johns Hopkins University, Baltimore, Maryland, United States
- Marten, Jonathan, MRC IGMM, University of Edinburgh, Edinburgh, United Kingdom
Group or Team Name
- CKDGen Consortium
Background
High serum urate levels are a cause of gout, an excruciating disease with suboptimal treatment affecting ~4% of the adult population in many developed countries. Patients with kidney disease have higher risk for gout. Genome-wide association studies (GWAS) of serum urate in European ancestries have identified 28 loci. Together the index SNPs at these loci explain <10% of the phenotypic variance, suggesting that additional loci remain to be identified.
Methods
We performed meta-analyses of serum urate GWAS among 288,649 individuals of European ancestry from 60 studies and of gout among 753,884 individuals of European ancestry from 17 studies using fixed-effect inverse variance weighting. To reveal independent signals of serum urate, we used GCTA model selection to identify independent variants (r2<0.01) in genome-wide significant urate loci (p<5x10-8). To prioritize significant urate-associated variants, we conducted finemapping by calculating posterior probabilities in each independent region based on the Wakefield Bayes factor and constructed credible sets with 99% probability of containing driver variants.
Results
Meta-analyses identified 123 genome-wide significant 1-Mb intervals associated with serum urate (genomic control factor: 1.04). Of these, 87 were not annotated to known serum urate loci, and 98% were associated with gout in the same direction. GCTA model selection identified 114 independent signals of urate in 99 genomic regions, which were merged from the 123 intervals when index SNPs in adjacent intervals were correlated (r2 > 0.2). Of these 114 independent signals, half of the 99% credible sets had <17 variants, and 25% had only one variant.
Conclusion
We identified 114 independent signals associated with serum urate among European ancestry individuals. The concordance in effect direction of urate index variants for gout are consistent with established causal role of urate in gout pathophysiology. Following up on these GWAS findings with functional studies will generate novel insight in serum urate regulation and potential treatment targets for lowering urate levels for the prevention of gout.
Funding
- NIDDK Support