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Objective:Few studies have evaluated the benefits of colorectal cancer(CRC)screening integrating both non-genetic and genetic risk factors.Here,we aimed to integrate an existing non-genetic risk model(QCancer-10)and a 139-variant polygenic risk score to evaluate the effectiveness of screening on CRC incidence and mortality.Methods:We applied the integrated model to calculate 10-year CRC risk for 430,908 participants in the UK Biobank,and divided the participants into low-,intermediate-,and high-risk groups.We calculated the screening-associated hazard ratios(HRs)and absolute risk reductions(ARRs)for CRC incidence and mortality according to risk stratification.Results:During a median follow-up of 11.03 years and 12.60 years,we observed 5,158 CRC cases and 1,487 CRC deaths,respectively.CRC incidence and mortality were significantly lower among screened than non-screened participants in both the intermediate-and high-risk groups[incidence:HR:0.87,95%confidence interval(CI):0.81-0.94;0.81,0.73-0.90;mortality:0.75,0.64-0.87;0.70,0.58-0.85],which composed approximately 60%of the study population.The ARRs(95%CI)were 0.17(0.11-0.24)and 0.43(0.24-0.61),respectively,for CRC incidence,and 0.08(0.05-0.11)and 0.24(0.15-0.33),respectively,for mortality.Screening did not significantly reduce the relative or absolute risk of CRC incidence and mortality in the low-risk group.Further analysis revealed that screening was most effective for men and individuals with distal CRC among the intermediate to high-risk groups.Conclusions:After integrating both genetic and non-genetic factors,our findings provided priority evidence of risk-stratified CRC screening and valuable insights for the rational allocation of health resources.