BACKGROUND Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD. METHODS We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and 28 879 controls and 2808 cases and 7261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the coronary artery disease genome-wide replication and meta-analysis plus the coronary artery disease 1000 Genomes meta-analysis with UK Biobank. We then explored the pathophysiological significance of these novel loci and examined the differences in CAD-susceptibility loci between Japanese and Europeans. RESULTS We identified 3 new loci on chromosome 1q21 (CTSS), 10q26 (WDR11-FGFR2), and 11q22 (RDX-FDX1). Quantitative trait locus analyses suggested the association of CTSS and RDX-FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands, and fat tissues in the development of CAD. We next compared the odds ratios of lead variants for myocardial infarction at 76 genome-wide significant loci in the transethnic meta-analysis and a moderate correlation between Japanese and Europeans, where 8 loci showed a difference. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans. CONCLUSIONS We identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.

中文翻译：

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全基因组关联研究的跨种族元分析确定了冠状动脉疾病的三个新位点并表征了人群特异性差异。

背景全基因组关联研究为冠状动脉疾病（CAD）提供了许多生物学见解，但这些研究主要在欧洲人中进行。不同人群的全基因组关联研究有可能促进我们对 CAD 的理解。方法 我们对日本人群中的 CAD 进行了 2 项全基因组关联研究，其中分别包括 12 494 例和 28 879 例对照以及 2808 例和 7261 例对照。然后，我们使用冠状动脉疾病全基因组复制和荟萃分析的结果以及与 UK Biobank 进行的冠状动脉疾病 1000 基因组荟萃分析进行了跨种族荟萃分析。然后我们探索了这些新基因座的病理生理学意义，并检查了日本人和欧洲人之间 CAD 易感基因座的差异。结果 我们在染色体 1q21 (CTSS)、10q26 (WDR11-FGFR2) 和 11q22 (RDX-FDX1) 上鉴定了 3 个新基因座。定量性状基因座分析表明 CTSS 和 RDX-FDX1 与动脉粥样硬化免疫细胞的关联。组织/细胞类型富集分析显示动脉、肾上腺和脂肪组织参与了 CAD 的发展。我们接下来比较了跨种族荟萃分析中 76 个全基因组显着位点心肌梗死的先导变异的优势比以及日本人和欧洲人之间的中等相关性，其中 8 个位点显示差异。最后，我们根据风险等位基因频率使用东亚频繁和欧洲频繁的变异进行了组织/细胞类型富集分析，并在东亚频繁组中发现了显着的肾上腺富集，而在东亚频繁组中发现了动脉和脂肪组织的富集。欧洲常客群。这些发现表明日本人和欧洲人在 CAD 易感性方面存在生物学差异。结论 我们确定了 3 个新的 CAD 位点，并强调了日本和欧洲人群之间的遗传差异。此外，我们的跨种族分析显示了日本人和欧洲人之间共享和独特的遗传结构。虽然 CAD 的大多数潜在遗传基础是共享的，但需要对不同人群进行进一步分析以充分阐明变异。