Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

Abstract

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

Figure 1

Multiple genomic loci contain SNPs associated with serum urate concentrations. Truncated Manhattan plot showing −log₁₀ (P values) for all SNPs of the urate discovery GWAS ordered by chromosomal position. The gene closest to the SNP with the lowest P value at each locus (index SNP) is listed. Loci in gray met one but not both replication criteria. Blue triangles represent loci containing SNPs with P values below 1 × 10⁻²⁵.

Figure 2

Minor alleles of all replicated GWAS loci show direction-consistent association with serum urate concentrations and the odds of gout. Loci with significant sex-specific effects are shown in red. Lines correspond to 95% confidence intervals. The Pearson’s correlation coefficient was calculated using the log odds ratio (ln(OR)) for gout.

Figure 3

SNP effects on urate concentrations (mg/dl) are similar among individuals of European ancestry, African-Americans, Indians and Japanese, whereas allele frequencies vary. Comparison of SNP effects at the replicated loci and at four additional loci meeting one of the replication criteria. Left, effects on serum urate concentrations per minor allele (defined in individuals of European ancestry) sorted by effect size. Right, comparison of allele frequencies across the four different samples. Symbols are absent if the data could not be provided for reasons related to allele frequency (not polymorphic, low minor allele frequency) or poor imputation quality.