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

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.

Genetics of atrial fibrillation

“…Although rare damaging variants in cardiomyopathy genes may be investigated through targeted sequencing, evaluating risk attributable to common variants relies on PRS, which aggregates an individual's genetic risk for acquiring a phenotype over millions of common genetic variants. An inverse correlation between high PRS risk and age of atrial fibrillation onset has also been observed [2 ▪▪ ], as well as an association between high atrial fibrillation PRS risk in individuals without a diagnosis of atrial fibrillation and increased risk of cerebral infarction and cardioembolic stroke in a recent trans-ancestry GWAS [2 ▪▪ ]. Taken together, results from these studies suggest there may be utility in genetic testing to improve atrial fibrillation risk stratification and in identifying individuals at risk for early-onset atrial fibrillation in a subset of individuals.…”

“…Of these new atrial fibrillation variants, two (rs202030113 near SYNE1 and rs778479352 in FGF13 ) had not been reported outside of East Asian populations. In a trans-ancestry meta-analysis of an additional 77 690 individuals with atrial fibrillation across several European and Finnish atrial fibrillation cohorts, a total of 35 novel atrial fibrillation loci not previously reported at the genome-wide significance level were identified (Table 1) [2 ▪▪ ], illustrating the continued utility of GWAS across multiple diverse population ancestries in uncovering new genetic atrial fibrillation associations.…”

“…Historically, the largest non-European atrial fibrillation GWAS published to date consisted of over 8180 individuals with and 28 612 without atrial fibrillation in a Japanese population [4]. Miyazawa et al [2 ▪▪ ] expand this work by comparing genetic variants in 9826 individuals with atrial fibrillation to 150 272 without atrial fibrillation using participants from BioBank Japan. Their study identified five new atrial fibrillation risk loci in the Japanese population, mapping to nearby genes SYNE1 , HCFC2 , ZNF689 , PTCHD1 , and FGF13 .…”

“…Over one hundred genetic loci have been linked to atrial fibrillation through several large genome-wide association studies (GWAS) [1,2 ▪▪ ]. These studies have illuminated the complex genetic architecture of atrial fibrillation and outlined biological processes key to its development.…”

“…Since then, additional atrial fibrillation risk loci have been linked to transcription, factors involved in cardiac development and tissue remodeling, ion channels involved in cardiac, electrical signaling, and structural components of cardiomyocytes that are also damaged in several inherited cardiomyopathies. The largest and most recently published GWAS consisted of a meta-analysis of 77 690 individuals with atrial fibrillation from over 50 studies, composed of individuals from predominantly European (78.0%) and Japanese (12.6%) ancestries [2 ▪▪ ]. In total, this study reported 149 genome-wide significant loci of which 32 were novel.…”