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. This study performed a genome-wide association study (GWAS) in the Japanese population and a cross-ancestry meta-analysis of >1 million individuals, identifying 35 new susceptibility loci. Transcriptome-wide association analysis identified *IL6R* as a putative causal gene, suggesting immune response involvement. Integrative analysis demonstrated *ERRγ*'s key role in AF-associated gene regulation. A polygenic risk score predicted increased cardiovascular and stroke mortality risks and identified individuals with cardioembolic stroke among undiagnosed AF patients. The results provide new biological and clinical insights into AF genetics and suggest clinical applications.
