背景：痛风是一种高度遗传性疾病，但并非所有携带众所周知的风险变异的人即使在高尿酸血症状态下也会发展为痛风发作。我们进行了全基因组关联研究（GWAS）和多基因风险评分（PRS）分析，以说明痛风和无症状高尿酸血症（AH）的新遗传结构。
方法：进行GWAS以确定与正常尿酸血症相比与痛风/AH相关的变异。参与者是男性，从台湾生物银行和中国医科大学注册，并分为发现组(n=39,594)和复制组(n=891)。对于PRS分析，发现队列分为基础队列(n=21,814)和目标队列(n=17,780)，并且通过将基础队列中表型的多态性分为保护性或非保护性来估计得分。
结果：发现ABCG2和SLC2A9基因是控制痛风和AH的主要遗传因素，甚至在那些携带rs2231142（ABCG2）野生基因型的人中。令人惊讶的是,1号染色体上的变异，如rs7546668（DNAJC16），rs10927807(AGMAT),rs9286836(NUDT17),rs4971100(TRIM46),rs4072037(MUC1),和rs2974935(MTX1)，在发现和复制队列中均显示与痛风的显着关联（所有p值<1e-8）。关于PRS，在那些对表型有风险影响的SNP中，痛风和AH的发生率随着四分位数PRS的增加而增加；相反，在这些保护性SNP中，痛风/AH率随着四分位数PRS的增加而降低。
结论：我们在1号染色体上发现了与痛风显著相关的新变异，和PRS根据SNP对性状的影响类型，更有力地预测发生痛风/AH的风险。
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.
