Cross-ancestry genome-wide analysis of atrial fibrillation unveils disease biology and enables cardioembolic risk prediction
Year: 2023
Type: review
Study design: Observational Study
Abstract: 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.
Source: Nature Genetics
Authors: Kazuo Miyazawa, Kaoru Ito, Masamichi Ito, Zhaonan Zou, Masayuki Kubota, Seitaro Nomura, Hiroshi Matsunaga, Satoshi Koyama, Hirotaka Ieki, Masato Akiyama, Yoshinao Koike, Ryo Kurosawa, Hiroki Yoshida, Kouichi Ozaki, Yoshihiro Onouchi, BioBank Japan Project, Koichi Matsuda, Yoshinori Murakami, Yoichiro Kamatani, Atsushi Takahashi, Koichi Matsuda, Yoshinori Murakami, Hiroyuki Aburatani, Michiaki Kubo, Yukihide Momozawa, Chikashi Terao, Shinya Oki, Hiroshi Akazawa, Yoichiro Kamatani, Issei Komuro
Institutions: RIKEN Center for Integrative Medical Sciences, The University of Tokyo, Kyoto University, Broad Institute, Massachusetts General Hospital, Kyushu University, Hokkaido University, Medical Genome Center, National Center for Geriatrics and Gerontology, Research Institute, National Center for Geriatrics and Gerontology, Chiba University, Institute of Medical Science, The University of Tokyo, National Cerebral and Cardiovascular Center, National Cerebral and Cardiovascular Center Research Institute, Research Center for Advanced Science and Technology, The University of Tokyo
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $11,690
Funders: Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, National Center for Geriatrics and Gerontology, Japan Society for the Promotion of Science, Japan Science and Technology Agency, RIKEN, National Bioscience Database Center, Precursory Research for Embryonic Science and Technology
Awards: Elucidating the modes of action of drugs using transcription factor binding profiles, 疾患関連遺伝子等の探索を効率化するための遺伝子多型情報の高度化, 全ゲノム解析と組織オミックス解析による心房細動の病態解明と精密医療, G1358769263, Multi-omics data analysis using machine learning for precision medicine in coronary artery disease, Elucidation of genetic factors that define myocardial vulnerability as a basis for the development of heart failure, Artificial intelligence-based genome analysis of coronary artery disease to realize precision health, G4385704767, Single-cell omics analysis to develop the therapy for heart failure via cardiomyocyte reprogramming, G5149198641, Molecular pathogenesis of endothelial oxidative stress-triggered formation of aortic aneurysm in Marfan syndrome, バイオバンクの構築と臨床情報データベース化, Comprehensive search and functional analysis for rare variants associated with coronary artery disease using a next-generation framework, Development of novel diagnostic and therapeutic approaches to cancer by analyzing specific features of the immunoglobulin superfamily of molecules., G6298565101, G665897744, Research for Risk Stratification of cerebral hemorrhage, DNA damage and senescence in cardiomyocytes for the development of heart failure, G6860943434, 次世代シークエンス技術と機械学習を用いた、心房細動の精密化医療実現のための研究, G7521232162, G8344125803, G8473438688, G964404522
OpenAlex ID: W4317366348