Direct-oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation, yet the genetic factors contributing to DOAC-associated bleeding remain largely unexplored. This study aimed to identify genetic variants related to DOAC- associated bleeding and evaluate their potential for bleeding risk prediction. Patients receiving DOACs for stroke prevention in atrial fibrillation were enrolled. Genomic DNA was extracted from blood samples and genotyped. To identify single nucleotide polymorphisms (SNPs) associated with bleeding, genome-wide association study (GWAS), pathway enrichment analysis (PEA), and linkage disequilibrium (LD) assessments were performed. Subsequently, polygenic risk score (PRS) system was constructed. A total of 98 participants were recruited, of whom 11 experienced bleeding events. A GWAS identified 371 SNPs for bleeding events, which were further refined to 12 candidate SNPs through PEA and LD assessment. The strongest associations were observed for rs79402775, rs4924450, and rs6681938 (β = 2.943, 2.450, and 2.311, respectively). Individuals with a high PRS showed a 12.77-fold increased risk of bleeding compared with those with a low PRS, even after adjustment for clinical variables. This study identified genetic variants related to DOAC-associated bleeding and demonstrated the potential of PRS for predicting bleeding risk. These findings may support precision medicine in DOAC therapy for patients with atrial fibrillation.