Polygenic risk score trend and new variants on chromosome 1 are associated with male gout in genome-wide association study

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BACKGROUND: Gout is a highly hereditary disease, but not all those carrying well-known risk variants have developing gout attack even in hyperuricemia status. We performed a genome-wide association study (GWAS) and polygenic risk score (PRS) analysis to illustrate the new genetic architectures of gout and asymptomatic hyperuricemia (AH). METHODS: GWAS was performed to identify variants associated with gout/AH compared with normouricemia. The participants were males, enrolled from the Taiwan Biobank and China Medical University, and divided into discovery (n=39,594) and replication (n=891) cohorts for GWAS. For PRS analysis, the discovery cohort was grouped as base (n=21,814) and target (n=17,780) cohorts, and the score was estimated by grouping the polymorphisms into protective or not for the phenotypes in the base cohort. RESULTS: The genes ABCG2 and SLC2A9 were found as the major genetic factors governing gouty and AH, and even in those carrying the rs2231142 (ABCG2) wild-genotype. Surprisingly, variants on chromosome 1, such as rs7546668 (DNAJC16), rs10927807 (AGMAT), rs9286836 (NUDT17), rs4971100 (TRIM46), rs4072037 (MUC1), and rs2974935 (MTX1), showed significant associations with gout in both discovery and replication cohorts (all p-values < 1e-8). Concerning the PRS, the rates of gout and AH increased with increased quartile PRS in those SNPs having risk effects on the phenotypes; on the contrary, gout/AH rates decreased with increased quartile PRS in those protective SNPs. CONCLUSIONS: We found new variants on chromosome 1 significantly relating to gout, and PRS predicts the risk of developing gout/AH more robustly based on the SNPs' effect types on the trait.

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