Assessment of Body Mass Index, Polygenic Risk Score, and Development of Colorectal Cancer

IMPORTANCE: Excess weight, the prevalence of which is high and increasing in many countries, is linked to multiple adverse health outcomes, including increased colorectal cancer (CRC) risk. Better communication of health risks associated with excess weight might support efforts of prevention. OBJECTIVE: To evaluate the individual and joint associations of body mass index (BMI) and polygenic risk with CRC, to assess potential interactions among them, and to quantify by how much increased polygenic risk for CRC can be offset by having a BMI within reference range. DESIGN, SETTING, AND PARTICIPANTS: This population-based case-control study was conducted in the Rhine-Neckar region of southwest Germany, with recruitment from 2003 to 2017. Participants with both risk factor and genetic information were included for analysis. Data analysis was conducted from December 8, 2021, to February 17, 2022. EXPOSURES: BMI was calculated as self-reported weight in kilograms approximately 10 years before diagnosis or interview and current height in meters squared. A polygenic risk score (PRS) was built based on 140 CRC-related risk loci. MAIN OUTCOMES AND MEASURES: Individual and joint associations of BMI and PRS with CRC were estimated using multiple logistic regression. Associations of excess weight with CRC were quantified by adjusted odds ratios (aORs) and genetic risk equivalents (GREs), the equivalent outcomes conveyed by defined differences in PRS percentiles. RESULTS: Among 9169 participants (median [IQR] age, 69 [62-76] years; 5589 [61.0%] male participants) included, 5053 had CRC and 4116 did not. BMI of 30 or greater was associated with higher odds of having CRC compared with BMI less than 25 (aOR, 1.71; 95% CI, 1.49-1.97), independent of PRS levels (P for interaction = .45). Participants with BMI of 30 or greater and a PRS in the highest tertile had higher odds of CRC compared with participants with BMI less than 25 and a PRS in the lowest tertile (aOR, 3.82; 95% CI, 3.03-4.82). The estimated association of BMI greater than 30 with CRC risk was equivalent to that of having a 41 (95% CI, 29-53)–percentile higher PRS. BMI of 30 or greater was particularly associated with stage IV CRC (aOR, 2.21; 95% CI, 1.71-2.84). CONCLUSIONS AND RELEVANCE: These findings suggest that excess weight was associated with CRC regardless of PRS levels. The association of having a BMI within reference range may be similar to that of having a substantially lower polygenic risk for CRC.