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<p>To understand the genetic basis of heart failure (HF) in the Japanese population, we performed genome-wide association studies (GWASs) comprising 16,251 all-cause HF cases, 4254 HF with reduced ejection fraction (HFrEF) cases, 7154 HF with preserved ejection fraction cases, and 11,122 non-ischemic HF cases among 213,828 individuals and identified five novel loci. A subsequent cross-ancestry meta-analysis and multi-trait analysis of the GWAS data identified 19 novel loci in total, with 31 out of the 76 genome-wide significant loci associated with HFrEF despite its smaller sample size. Among these susceptibility loci, a common non-coding variant in <i>TTN</i> (rs1484116) was associated with reduced cardiac function and worse long-term mortality. We leveraged the HF meta-GWASs along with cardiac function-related GWASs to develop a polygenic risk score (PRS) for HF. The PRS successfully identified early-onset HF and those with an increased risk of long-term HF mortality. Our results shed light on the shared and distinct genetic basis of HF between Japanese and European populations and improve the clinical value of HF genetics.</p>

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Genome-wide analysis of heart failure yields insights into disease heterogeneity and enables prognostic prediction in the Japanese population

  • 期刊论文

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  • 发表日期：

    2025年11月3日

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  • Nobuyuki Enzan,
  • Kazuo Miyazawa,
  • Satoshi Koyama,
  • Ryo Kurosawa,
  • Hirotaka Ieki,
  • Hiroki Yoshida,
  • Fumie Takechi,
  • Masashi Fukuyama,
  • Ryosuke Osako,
  • Kohei Tomizuka,
  • Xiaoxi Liu,
  • Kouichi Ozaki,
  • Yoshihiro Onouchi,
  • Koichi Matsuda,
  • Yukihide Momozawa,
  • Hiroyuki Aburatani,
  • Yoichiro Kamatani,
  • Takanori Yamaguchi,
  • Hiroshi Akazawa,
  • Koichi Node,
  • Patrick T. Ellinor,
  • Michael G. Levin,
  • Scott M. Damrauer,
  • Benjamin F. Voight,
  • Jacob Joseph,
  • Yan V. Sun,
  • Chikashi Terao,
  • Toshiharu Ninomiya,
  • Issei Komuro,
  • Kaoru Ito

摘要

To understand the genetic basis of heart failure (HF) in the Japanese population, we performed genome-wide association studies (GWASs) comprising 16,251 all-cause HF cases, 4254 HF with reduced ejection fraction (HFrEF) cases, 7154 HF with preserved ejection fraction cases, and 11,122 non-ischemic HF cases among 213,828 individuals and identified five novel loci. A subsequent cross-ancestry meta-analysis and multi-trait analysis of the GWAS data identified 19 novel loci in total, with 31 out of the 76 genome-wide significant loci associated with HFrEF despite its smaller sample size. Among these susceptibility loci, a common non-coding variant in TTN (rs1484116) was associated with reduced cardiac function and worse long-term mortality. We leveraged the HF meta-GWASs along with cardiac function-related GWASs to develop a polygenic risk score (PRS) for HF. The PRS successfully identified early-onset HF and those with an increased risk of long-term HF mortality. Our results shed light on the shared and distinct genetic basis of HF between Japanese and European populations and improve the clinical value of HF genetics.