Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: Results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank

Objectives: To perform a genome-wide association study (GWAS) of gout cases vs. asymptomatic hyperuricaemia (AH) controls, and gout cases vs. normouricaemia controls, and to generate a polygenic risk score (PRS) to determine gout-case vs. AH-control status.Methods: Gout cases and AH controls (serum urate (SU) ?6mg/dL) from the UK Biobank were divided into discovery (4,934 cases, 56,948 controls) and replication (2,115 cases, 24,406 controls) cohorts. GWAS was conducted and PRS generated using summary statistics in discovery cohort as the base dataset and the replication cohort as the target dataset. The predictive ability of the model was evaluated. GWAS were performed to identify variants associated with gout compared to normouricaemic controls using SU ? 6mg/dL) from the UK Biobank were divided into discovery (4,934 cases, 56,948 controls) and replication (2,115 cases, 24,406 controls) cohorts. GWAS was conducted and PRS generated using summary statistics in discovery cohort as the base dataset and the replication cohort as the target dataset. The predictive ability of the model was evaluated. GWAS were performed to identify variants associated with gout compared to normouricaemic controls using SU < 6.0 mg/dL and < 7.0 mg/dL thresholds respectively.Results: Thirteen independent SNPs in ABCG2, SLC2A9, SLC22A11, GCKR, MEPE, PPM1K-DT, LOC105377323, and ADH1B reached genome-wide significance and replicated as predictors of AH to gout transition. Twelve of 13 associations were novel for this transition, and rs1229984 (ADH1B) was identified as GWAS locus for gout for the first time. The best PRS model was generated from association data of 17 SNPs; and had predictive ability of 58.5% that increased to 69.2% upon including demographic factors. Two novel SNPs rs760077(MTX1) and rs3800307(PRSS16) achieved GWAS significance for association with gout compared with normouricaemic controls using both SU thresholds. Conclusion: The association of urate transporters with gout supports the central role of hyperuricaemia in its pathogenesis. Larger GWAS are required to identify if variants in inflammatory pathways contribute to progression from AH to gout