Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases.
Roselli C, Surakka I, Olesen MS et al.
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Abstract
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Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, 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 risk loci will facilitate a greater understanding of the pathways underlying AF.
1,782 Admix African and African American cases, 9,356 Admix African and African American controls, 11,350 East Asian ancestry cases, 137,515 East Asian ancestry controls, 166,322 European ancestry cases, 1,313,950 European ancestry controls, 1,774 Hispanic or Latin American cases, 7,665 Hispanic or Latin American controls, 218 South Asian ancestry cases, 413 South Asian ancestry controls
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