In the largest genetic study of cardiac arrhythmia to date, researchers led by Kazuo Miyazawa and Kaoru Ito at the RIKEN Center for Integrative Medical Sciences (IMS) in Japan report the discovery of several genes and individual genetic variations that are associated with the atrial fibrillation . Data from more than one million people were analyzed and polygenic risk scores were calculated based on the genetic data. The study was published in the scientific journal Nature Genetics .
The scores predicted atrial fibrillation, and even stroke and mortality, in at-risk individuals.
Summary Atrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of stroke. Despite the 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 rare East Asian-specific variants associated with FA. A cross-ancestry meta-analysis of more than 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 evaluation using cardiomyocytes derived from human induced pluripotent stem cells demonstrated that ERRg plays a key role in the transcriptional regulation of AF-associated genes. A polygenic risk score derived from cross-ancestry meta-analysis predicted higher risks of cardiovascular and stroke mortality and segregated individuals with cardioembolic stroke from patients with undiagnosed atrial fibrillation. Our results provide new biological and clinical insights into the genetics of AF and suggest its potential for clinical applications. |
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Atrial fibrillation occurs when the heart beats rapidly and irregularly, causing blood to pool in the atria. This increases the risk of blood clots forming in the heart and then traveling to the brain where they can block blood flow and cause a stroke. In addition to other conditions such as high blood pressure and diabetes, atrial fibrillation is associated with some genetic factors, but exactly how remains a mystery.
Researchers examined the genomes of more than 150,000 Japanese individuals and found 5 locations within our chromosomes, called genetic loci , that have never before been associated with atrial fibrillation. Among them, two include genetic variations unique to East Asian populations. A subsequent cross-ancestry meta-analysis of more than 1.2 million people, the same Japanese population along with those from two large European studies, yielded overall 150 critical genetic loci , including 35 that were new. Further analysis found more than 130 genes associated with these loci . Therefore, the probability that variations in one or more of these genes cause atrial fibrillation is high.
Genes are turned on and off as needed by special regulatory proteins called transcription factors . To find transcription factors that activate genes at loci associated with atrial fibrillation, the researchers performed an integrative analysis with epigenomic data, searching for proteins that bind to the newly discovered loci . The analysis yielded the transcription factor ERRg, which was associated with genes that regulate processes that occur within cardiac muscle cells.
However, an association is not proof of causality. To prove that overactive ERRg could be a direct cause of atrial fibrillation, the researchers grew human heart muscle cells in the lab and facilitated ERRg activity. They found reduced expression of several important genes related to cardiac function. Furthermore, cardiac muscle cells exhibited irregular heartbeats and prolonged contraction.
“Until now, it was not very clear which genes and how their transcriptional regulation is involved in the pathophysiology of atrial fibrillation,” says Kazuo Miyazawa, first author of the study. “In this study, we discovered a key mechanism by integrating genomic data with epigenomic and transcriptomic data.”
The polygenic risk score is a statistical tool used to predict a person’s genetic susceptibility to diseases. However, when these scores are derived from genetic data from one population, they have difficulty predicting risk in another population. By adding the new Japanese data to that from the European studies, the RIKEN IMS team was able to make better predictions. They found that the higher the score, the younger people were when they developed atrial fibrillation. Furthermore, the score was significantly associated with stroke, even in people who had not been diagnosed with atrial fibrillation, and could predict the occurrence of death from stroke.
“By applying our model to a person’s genome, we can find clinically undetectable cardiac arrhythmias or other related conditions,” explains Miyazawa. "This is critical, as finding people at risk before they have a stroke is the goal of any risk prediction analysis."
Simply being able to find people at risk for atrial fibrillation is just the first step. The new study also leads to ideas for treatment. As Miyazawa explains, "As we found that ERRg is likely critically involved in the pathogenesis of atrial fibrillation, it represents a potential target for pharmaceutical intervention for those identified as at risk."
In conclusion , our large-scale Japanese and cross-ancestry genetic analyzes identified 35 new risk loci and provided insights into the distinct and shared genetic architecture of AF between Japanese and Europeans. Integrative analysis of transcriptome and epigenome data highlighted candidate genes and implicated a transcription factor involved in the mechanism of disease development. Furthermore, analyzes of disease prediction and long-term survival demonstrated the clinical utility of AF-PRS. These data highlight the importance of AF genetics in clinical settings and provide useful evidence for the implementation of genomic medicine.
