Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease
Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease
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DOI：
10.1161/circgen.119.002670
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发表时间：
2020-06-01
影响因子：
7.4
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Matsunaga, Hiroshi;Ito, Kaoru;Komuro, Issei
背景资料：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。研究方法：我们在日本人群中进行了2项CAD全基因组关联研究，其中分别包括12494例病例和28879例对照以及2808例病例和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UK Biobank的冠状动脉疾病1000个基因组荟萃分析进行了跨种族荟萃分析。然后，我们探讨了这些新的基因座的病理生理学意义，并研究了日本人和欧洲人之间CAD易感基因座的差异。结果：在染色体1 q21（CTSS）、10 q26（WDR 11-FGFR 2）和11 q22（RDX-FDX 1）上发现3个新的基因座。数量性状位点分析提示CTSS和RDX-FDX 1与动脉粥样硬化免疫细胞相关。组织/细胞类型富集分析显示动脉、肾上腺和脂肪组织参与CAD的发展。接下来，我们在跨种族荟萃分析中比较了76个全基因组显著位点的心肌梗死导联变异的优势比，以及日本人和欧洲人之间的中度相关性，其中8个位点显示出差异。最后，我们根据危险等位基因频率使用东亚常见和欧洲常见变体进行了组织/细胞类型富集分析，并在东亚常见组中发现了肾上腺的显著富集，而在欧洲常见组中发现了动脉和脂肪组织的富集。这些发现表明日本人和欧洲人之间CAD易感性的生物学差异。结论：我们发现了3个新的CAD基因座，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，日本人和欧洲人之间既有共同的遗传结构，也有独特的遗传结构。虽然大多数CAD的潜在遗传基础是共享的，但需要在不同人群中进行进一步分析以充分阐明变异。
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 ofCTSSandRDX-FDX1with 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.