Objectives Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000–3000 years. Methods Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. Results In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10–8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients’ gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. Conclusions Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

中文翻译：

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通过临床定义痛风患者的亚型全基因组荟萃分析确定的亚型特异性痛风易感基因座和 ABCG2 和 ALDH2 选择压力的富集

目的 对临床定义的痛风进行全基因组荟萃分析，以确定亚型特异性易感基因座。还对这些基因座使用选择压力分析进行了评估，以调查过去 2000-3000 年日本人口的遗传风险特征。方法 使用 Japonica Array 和 Illumina Array 平台对来自日本男性的 3053 例临床定义的痛风病例和 4554 例对照进行了两项全基因组关联研究 (GWAS)。在插补后对大约 720 万个单核苷酸多态性进行了荟萃分析。然后将患者分为四种临床亚型（肾排泄不足型、肾超负荷型、合并型和正常型），并以相同的方式进行荟萃分析。还对每个亚型进行了使用单例密度评分的选择压力分析。结果 除了我们之前报道的 8 个基因座外，在所有痛风患者的 GWAS 荟萃分析中，在全基因组显着性水平（p<5.0×10-8）和其他来自正常型痛风患者的两个新的基因间基因座，CD2-PTGFRN 和 SLC28A3-NTRK2。在痛风患者的亚型 GWAS 中观察到曼哈顿图的亚型依赖性模式，表明这些亚型特异性基因座表明患者痛风亚型的病理生理学存在差异。选择压力分析显示，除了正常型痛风之外的所有亚型，除了 ALDH2 基因座外，ABCG2 上的选择压力显着富集。