Background:The underlying etiology of colorectal cancer (CRC) includes both genetic variation and environmental exposures. The main aim of this study was to search for interaction effects between well-established environmental risk factors and published common genetic variants exerting main effects on CRC risk. Methods:We used a two-phase approach: (i) Discovery phase (2,652 incident CRC cases and 10,608 controls from UK Biobank) and (ii) Validation phase (1,656 cases and 2,497 controls from the Study of Colorectal Cancer in Scotland). Interactions with nominal P<0.05 in phase I were taken forward for validation in phase II. Furthermore, we constructed a weighted genetic risk score (GRS) of CRC risk for each individual and studied interactions between the GRS and the environmental risk factors. Results:Seventy of the 1,500 tested interactions were nominally significant in phase I. After testing these 70 interactions in phase II, an interaction between rs11903757 (2q32.3/NABP1) and body mass index (BMI) was nominally significant (P=0.02) with the same direction of effects. The rs11903757*BMI interaction was also significant (ratio of odds ratios =1.26; 95% CI, 1.10-1.44; Pinteraction=6.03×10-4; Pheterogeneity=0.63) in a meta-analysis combining results from both phases. No interactions were significant in phase II after accounting for multiple testing. No interactions involving the GRS were found with statistical significance. Conclusions:Limited evidence of gene-environment interactions in CRC risk was observed. There are potential modifications of the rs11903757 effect by BMI on CRC risk. Impact:Our findings might contribute to identifying subpopulations with different susceptibility to the effect of BMI on CRC risk.