To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations.

为了阐明日本人群中冠状动脉疾病（CAD）的遗传学，我们使用了一个新开发的参考小组，对168,228名日本血统（25,892例病例和142,336例对照）个体与基因型推算进行了大规模的全基因组关联研究。日本单倍型，包括1,781个CAD病例和2,636个对照。我们检测到八个新的易感基因座和日本特有的罕见变异，这些变异导致疾病的严重程度和心血管死亡率的增加。然后，我们进行了跨祖先的荟萃分析，并发现了35个新的新基因座。使用荟萃分析结果，我们得出了CAD的多基因风险评分（PRS），该结果优于日本或欧洲全基因组关联研究得出的结果。PRS在各种临床参数中将危险因素放在了优先位置，并且将个体与长期心血管疾病的死亡率增加了风险。我们的数据改善了CAD遗传学的临床特征，并提出了跨谱系荟萃分析在非欧洲人群中进行PRS推导的实用性。