This study aimed to identify rare predicted loss-of-function (pLOF) variants associated with atrial fibrillation (AF) and to elucidate their role in AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS). The study utilized data from the UK Biobank, including 403,990 individuals aged 40 to 69 years, with a median follow-up of 13.3 years. Rare pLOF variants in six genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF, with TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicating in an external cohort. Combined with a high PRS, these variants conferred a significant increase in the odds ratio for AF. Carriers with high PRS also had a substantial 10-year risk of AF. Rare pLOF variants were associated with increased risk of CM both before and after AF diagnosis. The findings suggest that rare and common genetic variations contribute to the genetic underpinnings of AF and may aid in future genetic risk stratification.This study aimed to identify rare predicted loss-of-function (pLOF) variants associated with atrial fibrillation (AF) and to elucidate their role in AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS). The study utilized data from the UK Biobank, including 403,990 individuals aged 40 to 69 years, with a median follow-up of 13.3 years. Rare pLOF variants in six genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF, with TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicating in an external cohort. Combined with a high PRS, these variants conferred a significant increase in the odds ratio for AF. Carriers with high PRS also had a substantial 10-year risk of AF. Rare pLOF variants were associated with increased risk of CM both before and after AF diagnosis. The findings suggest that rare and common genetic variations contribute to the genetic underpinnings of AF and may aid in future genetic risk stratification.