This study investigates the genetic factors underlying atrial fibrillation (AF) risk, focusing on both rare and common genetic variations. Using data from the UK Biobank, researchers identified rare predicted loss-of-function (pLOF) variants in six genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) associated with AF. These variants were linked to an increased risk of AF, cardiomyopathy, and heart failure. When combined with a polygenic risk score (PRS), rare pLOF variants significantly increased the risk of AF, with an odds ratio of 7.08. Carriers with high PRS had a substantial 10-year risk of AF, particularly in older individuals. Rare pLOF variants were also associated with increased risk of cardiomyopathy, both before and after AF diagnosis. The study highlights the importance of both rare and common genetic variations in AF risk. It suggests that integrating rare and common genetic variants into risk stratification could improve AF prevention and management. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk assessment. The study also found that rare pLOF variants in AF-associated genes were associated with increased risks of heart failure and cardiomyopathy. However, the association with cardiomyopathy was less pronounced when excluding TTN variants. The study also examined the combined effect of AF PRS and clinical risk factors, such as obesity and hypertension, and found that individuals with high PRS and these risk factors had a higher risk of AF. The study has limitations, including the focus on individuals of European ancestry and the potential for population stratification. Additionally, the strict significance threshold used may have limited the detection of potential genes associated with AF. Despite these limitations, the study provides valuable insights into the genetic factors underlying AF and highlights the potential of integrating rare and common genetic variations into risk stratification strategies. The findings may contribute to a better understanding of specific genes in which rare pLOF variants convey a large risk of AF and may aid in future genetic risk assessment.This study investigates the genetic factors underlying atrial fibrillation (AF) risk, focusing on both rare and common genetic variations. Using data from the UK Biobank, researchers identified rare predicted loss-of-function (pLOF) variants in six genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) associated with AF. These variants were linked to an increased risk of AF, cardiomyopathy, and heart failure. When combined with a polygenic risk score (PRS), rare pLOF variants significantly increased the risk of AF, with an odds ratio of 7.08. Carriers with high PRS had a substantial 10-year risk of AF, particularly in older individuals. Rare pLOF variants were also associated with increased risk of cardiomyopathy, both before and after AF diagnosis. The study highlights the importance of both rare and common genetic variations in AF risk. It suggests that integrating rare and common genetic variants into risk stratification could improve AF prevention and management. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk assessment. The study also found that rare pLOF variants in AF-associated genes were associated with increased risks of heart failure and cardiomyopathy. However, the association with cardiomyopathy was less pronounced when excluding TTN variants. The study also examined the combined effect of AF PRS and clinical risk factors, such as obesity and hypertension, and found that individuals with high PRS and these risk factors had a higher risk of AF. The study has limitations, including the focus on individuals of European ancestry and the potential for population stratification. Additionally, the strict significance threshold used may have limited the detection of potential genes associated with AF. Despite these limitations, the study provides valuable insights into the genetic factors underlying AF and highlights the potential of integrating rare and common genetic variations into risk stratification strategies. The findings may contribute to a better understanding of specific genes in which rare pLOF variants convey a large risk of AF and may aid in future genetic risk assessment.