Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease
Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease
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DOI：
10.1038/s41588-020-0705-3
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发表时间：
2020-10-05
期刊：
影响因子：
30.8
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Koyama, Satoshi;Ito, Kaoru;Komuro, Issei
为了阐明日本人群冠状动脉疾病 (CAD) 的遗传学，我们对 168,228 名日本血统个体（25,892 例病例和 142,336 例对照）进行了大规模全基因组关联研究，并使用新开发的日本单倍型参考组（包括 1,781 例 CAD 病例和 2,636 例对照）进行基因型插补。我们检测到八个新的易感位点和日本特有的罕见变异，导致疾病严重程度和心血管死亡率增加。然后我们进行了跨祖先荟萃分析，发现了另外 35 个新基因座。利用荟萃分析结果，我们得出了 CAD 的多基因风险评分 (PRS)，该评分优于日本或欧洲全基因组关联研究得出的评分。 PRS 在各种临床参数中优先考虑危险因素，并隔离长期心血管死亡风险增加的个体。我们的数据改善了 CAD 遗传学的临床特征，并表明跨祖先荟萃分析在非欧洲人群中用于 PRS 衍生的实用性。日本人群的全基因组关联分析和跨祖先荟萃分析确定了冠状动脉疾病的新风险位点。根据这些发现得出的多基因风险评分可识别长期心血管死亡风险增加的个体。
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.Genome-wide association analyses in the Japanese population and trans-ancestry meta-analyses identify new risk loci for coronary artery disease. A polygenic risk score derived from these findings identifies individuals with increased risk of long-term cardiovascular mortality.