Meta-analysis of Genome-wide Associations and Polygenic Risk Prediction for Atrial Fibrillation in More Than 180,000 Cases

Atrial fibrillation (AF) is the most common abnormality of heart rhythm and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies (GWAS) increased the power to detect single-nucleotide variant (SNV) associations, and we report more than 350 AF-associated genetic loci. At 139 loci we identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication. We next assayed chromatin accessibility by ATAC-seq and histone H3 Lysine 4 trimethylation in stem cell derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility of our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, we found that a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known AF risk loci will facilitate a greater understanding of the pathways underlying this heart rhythm disorder. Human pluripotent stem (hPSCs) cells were differentiated to atrial-like cardiomyocytes and subjected to ATAC-seq and H3K4me3 CUT&RUN.