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

• Published in: Nature genetics Vol. 55; no. 2; pp. 187 - 197
• Main Authors: 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, Takahashi, Atsushi, Matsuda, Koichi, Murakami, Yoshinori, Aburatani, Hiroyuki, Kubo, Michiaki, Momozawa, Yukihide, Terao, Chikashi, Oki, Shinya, Akazawa, Hiroshi, Kamatani, Yoichiro, Komuro, Issei
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2023; Nature Publishing Group
• Subjects: 14/63; 38/90; 45/100; 45/43; 631/208/205/2138; 631/208/457; 692/699/75/29/1309; Agriculture; Animal Genetics and Genomics; Arrhythmia; Association analysis; Atrial Fibrillation - genetics; Biological effects; Biology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cardiac arrhythmia; Cardiomyocytes; Datasets; Etiology; Fibrillation; Gene expression; Gene Function; Gene regulation; Genetic Predisposition to Disease; Genetics; Genome, Human; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Health risks; Heart; Human Genetics; Humans; Immune response; Induced Pluripotent Stem Cells; Interleukin 6 receptors; Meta-analysis; Pluripotency; Polymorphism, Single Nucleotide - genetics; Population studies; Risk; Statistical power; Stem cells; Stroke; Stroke - genetics; Transcriptomes
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-022-01284-9

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. Genome-wide analyses in BioBank Japan and populations of European ancestry identify new risk loci for atrial fibrillation. A polygenic risk score constructed from the cross-ancestry meta-analysis is associated with increased risk of long-term cardiovascular mortality.