Cross-ancestry genome-wide analysis of atrial fibrillation unveils disease biology and enables cardioembolic risk prediction

Autor: Miyazawa, Kazuo, Ito, Kaoru, Ito, Masamichi, Zou, Zhaonan, Kubota, Masayuki, Nomura, Seitaro, Matsunaga, Hiroshi, Koyama, Satoshi, Ieki, Hirotaka, Akiyama, Masato, Koike, Yoshinao, Kurosawa, Ryo, Yoshida, Hiroki, Ozaki, Kouichi, Onouchi, Yoshihiro, BioBank Japan Project, Takahashi, Atsushi, Matsuda, Koichi, Murakami, Yoshinori, Aburatani, Hiroyuki, Kubo, Michiaki, Momozawa, Yukihide, Terao, Chikashi, Oki, Shinya, Akazawa, Hiroshi, Kamatani, Yoichiro, Komuro, Issei
Rok vydání: 2023
Předmět:
Zdroj: Nature Genetics. 55:187-197
ISSN: 1546-1718
1061-4036
Popis: Atrial fibrillation (AF) is a common cardiac arrhythmia resulting in increased risk of stroke. Despite highly heritable etiology, our understanding of the genetic architecture of AF remains incomplete. Here we performed a genome-wide association study in the Japanese population comprising 9, 826 cases among 150, 272 individuals and identified East Asian-specific rare variants associated with AF. A cross-ancestry meta-analysis of >1 million individuals, including 77, 690 cases, identified 35 new susceptibility loci. Transcriptome-wide association analysis identified IL6R as a putative causal gene, suggesting the involvement of immune responses. Integrative analysis with ChIP-seq data and functional assessment using human induced pluripotent stem cell-derived cardiomyocytes demonstrated ERRg as having a key role in the transcriptional regulation of AF-associated genes. A polygenic risk score derived from the cross-ancestry meta-analysis predicted increased risks of cardiovascular and stroke mortalities and segregated individuals with cardioembolic stroke in undiagnosed AF patients. Our results provide new biological and clinical insights into AF genetics and suggest their potential for clinical applications.
心房細動の遺伝的基盤を解明 --大規模ゲノムデータによる病態解明と遺伝的リスクスコア構築--. 京都大学プレスリリース. 2023-01-20.
Databáze: OpenAIRE
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