Trans-ancestry genome-wide analysis of atrial fibrillation provides new insights into disease biology and enables polygenic prediction of cardioembolic risk
Trans-ancestry genome-wide analysis of atrial fibrillation provides new insights into disease biology and enables polygenic prediction of cardioembolic risk
复制标题
DOI：
10.1101/2021.09.06.21263189
复制
发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
K. Miyazawa;K. Ito;Zhaonan Zou;Hiroshi Matsunaga;S. Koyama;H. Ieki;S. Nomura;M. Akiyama;Ryo Kurosawa;Hiroki Yoshida;K. Ozaki;Y. Onouchi;A. Takahashi;K. Matsuda;Y. Murakami;H. Aburatani;M. Kubo;Y. Momozawa;C. Terao;Shinya Oki;H. Akazawa;Y. Kamatani;I. Komuro
中科院分区：
文献类型：
--
作者：
K. Miyazawa;K. Ito;Zhaonan Zou;Hiroshi Matsunaga;S. Koyama;H. Ieki;S. Nomura;M. Akiyama;Ryo Kurosawa;Hiroki Yoshida;K. Ozaki;Y. Onouchi;A. Takahashi;K. Matsuda;Y. Murakami;H. Aburatani;M. Kubo;Y. Momozawa;C. Terao;Shinya Oki;H. Akazawa;Y. Kamatani;I. Komuro
为了了解日本人群心房颤动 (AF) 的遗传基础，我们进行了一项大规模全基因组关联研究，包括 150,272 名个体中的 9,826 例 AF 病例，并确定了 5 个新的易感基因座，包括东亚特有的罕见变异。对超过 100 万人（包括 77,690 例病例）的跨血统荟萃分析确定了 35 个新基因座。利用基因表达和表观基因组数据集对假定的因果基因及其转录因子进行优先排序，揭示了除已知基因外，IL6R 基因和转录因子 ERG 的参与。此外，我们利用跨祖先荟萃分析构建了 AF 的多基因风险评分 (PRS)。 PRS 与长期心血管和中风死亡风险增加相关，并且在未确诊的 AF 患者中隔离患有心源性中风的个体。我们的结果为 AF 遗传学提供了新颖的生物学和临床见解，并表明了它们的临床应用潜力。
To understand the genetic underpinnings of atrial fibrillation (AF) in the Japanese population, we performed a large-scale genome-wide association study comprising 9,826 cases of AF among 150,272 individuals and identified five new susceptibility loci, including East Asian-specific rare variants. A trans-ancestry meta-analysis of >1 million individuals, including 77,690 cases, identified 35 novel loci. Leveraging gene expression and epigenomic datasets to prioritize putative causal genes and their transcription factors revealed the involvement of IL6R gene and transcription factor ERG besides the known ones. Further, we constructed a polygenic risk score (PRS) for AF, using the trans-ancestry meta-analysis. PRS was associated with an increased risk of long-term cardiovascular and stroke mortality, and segregated individuals with cardioembolic stroke in undiagnosed AF patients. Our results provide novel biological and clinical insights into AF genetics and suggest their potential for clinical applications.