In a new study published in Nature, researchers have identified 35 genetic susceptibility loci for atrial fibrillation (AF) in a Japanese population. The study also found that oestrogen-related receptor gamma (ERRg) plays a key role in the transcriptional regulation of AF-associated genes.
The need for non-European genomics studies
Atrial fibrillation is the most common type of cardiac arrhythmia, in which the upper chambers of the heart (the atria) beat irregularly and out of coordination with the lower chambers (the ventricles). This results in a lack of effective blood flow to the rest of the body and increases the risk of stroke and other complications. The genetic contribution to the development of AF is widely recognized, but the majority of studies have been performed in European populations. This study aimed to explore the genetic architecture of AF in a non-European population and improve the statistical power of AF-GWASs.
The findings of the study
The study identified five new risk loci for atrial fibrillation in the Japanese population through a genome-wide association study (GWAS). The GWAS was performed on a case-control dataset from BioBank Japan, which included 9,826 AF cases and 140,446 controls and used over 16 million variants in the autosomes and X chromosome. The study then replicated the five newly identified loci in an independent Japanese cohort, and all lead variants showed nominal associations in the same direction.
Furthermore, a cross-ancestry meta-analysis was conducted by combining the current Japanese GWAS and previous GWASs on AF, which identified 33 new risk loci for AF. Researchers also performed a transcriptome-wide association study (TWAS) using identified loci from the cross-ancestry meta-analysis and GTEx (The Genotype-Tissue Expression project) data to identify candidate genes associated with atrial fibrillation. The study found that ERRg binding was substantially enriched in AF-associated loci, and that ERRg is functionally involved in the pathogenesis of AF.
The study then evaluated the performance of a polygenic risk score (PRS) derived from various combinations of summary statistics in the Japanese population. The study split the case-control samples into derivation, validation, and test datasets and constructed 376 combinations of the summary statistics of three GWASs (BioBank Japan, EUR and FIN) with parameters for PRS derivation. Based on the PRS performance in the validation cohort, the study determined the parameters that showed the best predictive performance for the test dataset. The study found that the PRS derived from the combination of BioBank Japan and EUR summary statistics showed the best performance in terms of discrimination, calibration and reclassification, with an area under the curve (AUC) of 0.78 and 0.77 for the validation and test datasets, respectively.
Implications and future directions
The findings of this study have important implications for the future of research into atrial fibrillation. By identifying new genetic susceptibility loci and genes associated with atrial fibrillation in the Japanese population, the study has improved our understanding of the genetic pathophysiology of atrial fibrillation in non-European populations – and increased diversity is needed in genomics studies across the field. The use of the polygenic risk score can also be a potentially helpful tool to predict the risk of AF and could lead to improved diagnostic methods and better-targeted therapies for AF in the future.
