Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease

Hiroshi Matsunaga, Kaoru Ito, Masato Akiyama, Atsushi Takahashi, Satoshi Koyama, Seitaro Nomura, Hirotaka Ieki, Kouichi Ozaki, Yoshihiro Onouchi, Saori Sakaue, Shinichiro Suna, Soichi Ogishima, Masayuki Yamamoto, Atsushi Hozawa, Mamoru Satoh, Makoto Sasaki, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Shoichiro TsuganeKeitaro Tanaka, Kokichi Arisawa, Hiroaki Ikezaki, Naoyuki Takashima, Mariko Naito, Kenji Wakai, Hideo Tanaka, Yasuhiko Sakata, Hiroyuki Morita, Yasushi Sakata, Koichi Matsuda, Yoshinori Murakami, Hiroshi Akazawa, Michiaki Kubo, Yoichiro Kamatani, Issei Komuro

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)e002670
JournalCirculation. Genomic and precision medicine
Volume13
Issue number3
DOIs
Publication statusPublished - Jun 1 2020

All Science Journal Classification (ASJC) codes

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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    Matsunaga, H., Ito, K., Akiyama, M., Takahashi, A., Koyama, S., Nomura, S., Ieki, H., Ozaki, K., Onouchi, Y., Sakaue, S., Suna, S., Ogishima, S., Yamamoto, M., Hozawa, A., Satoh, M., Sasaki, M., Yamaji, T., Sawada, N., Iwasaki, M., ... Komuro, I. (2020). Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease. Circulation. Genomic and precision medicine, 13(3), e002670. https://doi.org/10.1161/CIRCGEN.119.002670