Excess weight, polygenic risk score and findings of colorectal neoplasms at screening colonoscopy

Introduction: Excess weight is an established risk factor for colorectal cancer (CRC). However, evidence is lacking on how its impact varies by polygenic risk at different stages of colorectal carcinogenesis. Methods: We assessed the individual and joint associations of body mass index (BMI) and polygenic risk scores (PRSs) with findings of colorectal neoplasms among 4,784 participants of screening colonoscopy. Adjusted odds ratios (aORs) for excess weight derived by multiple logistic regression were converted to genetic risk equivalents (GREs) to quantify the impact of excess weight compared to genetic predisposition. Results: Overweight and obesity ( BMI 25-<30 and ≥30 kg/m 2 ) were associated with increased risk of any colorectal neoplasm (aOR [95% CI] 1.26 [1.09-1.45] and 1.47 [1.24-1.75]). Obesity was associated with increased risk of advanced colorectal neoplasm (aOR [95% CI] 1.46 [1.16-1.84]). Dose-response relationships were seen for the PRS (stronger for advanced neoplasms than any neoplasms), with no interaction with BMI, suggesting multiplicative effects of both factors. Obese participants with a PRS in the highest tertile had a 2.3-fold (95% CI 1.7-3.1) and 2.9-fold (95%CI 1.9-4.3) increased risk of any colorectal neoplasm and advanced colorectal neoplasm, respectively. The aOR of obesity translated into a GRE of 38, meaning that its impact was estimated to be equivalent to the risk caused by 38 percentiles higher PRS for colorectal neoplasm. Conclusion: Excess weight and polygenic risk are associated with increased risk of colorectal neoplasms in a multiplicative manner. Maintaining normal weight is estimated to have an equivalent effect as having 38 percentiles lower PRS.