Genetically predicted physical activity levels are associated with lower colorectal cancer risk: a Mendelian randomisation study

Abstract

Background: We conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated through changes in body fat.

Methods: Common genetic variants associated with self-reported moderate-to-vigorous PA (MVPA), acceleration vector magnitude PA (AMPA) and sedentary time were used as instrumental variables. To control for confounding effects of obesity, we included instrumental variables for body mass index (BMI), body fat percentage, waist circumference and arm, trunk and leg fat ratios. We analysed the effect of these instrumental variables in a colorectal cancer genome-wide association study comprising 31,197 cases and 61,770 controls of European ancestry by applying two-sample and multivariable MR study designs.

Results: We found decreased colorectal cancer risk for genetically represented measures of MVPA and AMPA that were additional to effects mediated through genetic measures of obesity. Odds ratio and 95% confidence interval (CI) per standard deviation increase in MVPA and AMPA was 0.56 (0.31, 1.01) and 0.60 (0.41, 0.88), respectively. No association has been found between sedentary time and colorectal cancer risk. The proportion of effect mediated through BMI was 2% (95% CI: 0, 14) and 32% (95% CI: 12, 46) for MVPA and AMPA, respectively.

Conclusion: These findings provide strong evidence to reinforce public health measures on preventing colorectal cancer that promote PA at a population level regardless of body fatness.

Fig. 1. Schematic representation of the study design.

MAF minor allele frequency, LD linkage disequilibrium, MVPA self-reported moderate-to-vigorous physical activity, AMPA acceleration vector magnitude physical activity, BMI body mass index.

Fig. 2. Forest plot of two-sample Mendelian randomisation studies exploring associations between exposures to colorectal cancer risk.

MVPA self-reported moderate-to-vigorous physical activity, AMPA acceleration vector magnitude physical activity at P < 5 × 10⁻⁸, AMPA* acceleration vector magnitude physical activity at P < 5 × 10⁻⁹, BMI body mass index, OR odds ratio, CI confidence interval, IVW inverse variant-weighted method, P P value for random effect IVW result.

Fig. 3. Genetic correlation coefficient between each covariate.

MVPA self-reported moderate-to-vigorous physical activity, AMPA acceleration vector magnitude physical activity, BMI body mass index, CRC colorectal cancer, AFR arm fat ratio, LFR leg fat ratio, TFR trunk fat ratio.

Fig. 4. Proportion estimates through BMI and body fat composition.

BMI body mass index, MVPA self-reported moderate-to-vigorous physical activity, AMPA acceleration vector magnitude physical activity, AFR arm fat ratio, WC waist circumference, AMPA vs AFR the proportion of effects of AMPA on colorectal cancer risk mediated through AFR, AMPA vs BMI the proportion of effects of AMPA on colorectal cancer risk mediated through BMI, AMPA vs WC the proportion of effects of AMPA on colorectal cancer risk mediated through WC, MVPA vs AFR: the proportion of effects of AMPA on colorectal cancer risk mediated through AFR, MVPA vs BMI the proportion of effects of AMPA on colorectal cancer risk mediated through BMI.