Gout is a complex inflammatory arthritis affecting ~20% of people with an elevated serum urate level (hyperuricemia). Gout and hyperuricemia are essentially specific to humans and other higher primates, with varied prevalence across ancestral groups. SLC2A9 and ABCG2 are major loci associated with both urate and gout in multiple ancestral groups. However, fine mapping has been challenging due to extensive linkage disequilibrium underlying the associated regions. We used trans-ancestral fine mapping integrated with primate-specific genomic information to address this challenge. Trans-ancestral meta-analyses of GWAS cohorts of either European (EUR) or East Asian (EAS) ancestry resulted in single-variant resolution mappings for SLC2A9 (rs3775948 for urate and rs4697701 for gout) and ABCG2 (rs2622621 for gout). Tests of colocalization of variants in both urate and gout suggested existence of a shared candidate causal variant for SLC2A9 only in EUR and for ABCG2 only in EAS. The fine-mapped gout variant rs4697701 was within an ancient enhancer, whereas rs2622621 was within a primate-specific transposable element, both supported by functional evidence from the Roadmap Epigenomics project in human primary tissues relevant to urate and gout. Additional primate-specific elements were found near both loci and those adjacent to SLC2A9 overlapped with known statistical epistatic interactions associated with urate as well as multiple super-enhancers identified in urate-relevant tissues. We conclude that by leveraging ancestral differences trans-ancestral fine mapping has identified ancestral and functional variants for SLC2A9 or ABCG2 with primate-specific regulatory effects on urate and gout.

痛风是一种复杂的炎性关节炎，约有20％的人血清尿酸水平升高（高尿酸血症）。痛风和高尿酸血症本质上是人类和其他高等灵长类动物特有的，在祖先人群中患病率各异。SLC2A9和ABCG2是与多个祖先组的尿酸盐和痛风相关的主要基因座。然而，由于相关区域下的广泛连锁不平衡，精细定位一直具有挑战性。我们使用跨祖先精细映射与灵长类特有的基因组信息相集成来解决这一挑战。欧洲（EUR）或东亚（EAS）祖先的GWAS队列的祖先荟萃分析导致SLC2A9的单变量分辨率映射（对于尿酸盐来说是rs3775948，对于痛风来说是rs4697701）和ABCG2（对于痛风来说是rs2622621）。在尿酸盐和痛风中对变体进行共定位测试表明，仅在欧元中存在SLC2A9且在EAS中仅存在ABCG2的共有候选因果变体。精细映射的痛风变体rs4697701位于古老的增强子中，而rs2622621位于灵长类特定的转座因子之内，这都得到了路线图表基因组学计划中与尿酸和痛风有关的人类原发组织的功能性证据的支持。在位点附近和与SLC2A9相邻的位点附近都发现了其他灵长类特异性元件与与尿酸盐有关的已知统计上位相互作用以及在与尿酸盐相关的组织中鉴定出的多种超级增强剂重叠。我们得出的结论是，通过利用祖先差异，祖先精细作图已鉴定出SLC2A9或ABCG2的祖先和功能变体，对尿酸盐和痛风具有灵长类特异性调节作用。