ImportanceEvidence on adiposity altering colorectal cancer (CRC) risk differently among men and women, and on metabolic alterations mediating effects of adiposity on CRC, is unclear. ObjectiveTo examine sex- and site-specific associations of adiposity with CRC risk, and whether adiposity-associated metabolites explain associations of adiposity with CRC. DesignTwo-sample Mendelian randomization (MR) study. SettingGenetic variants from expanded genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N=806,810), and 123 metabolites (mostly lipoprotein subclass-specific lipids) from targeted nuclear magnetic resonance metabolomics (N=24,925), were used as instruments. Sex-combined and sex-specific MR was conducted for BMI and WHR with CRC risk; sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes. Participants58,221 cases and 67,694 controls (Genetics and Epidemiology of Colorectal Cancer Consortium; Colorectal Cancer Transdisciplinary Study; Colon Cancer Family Registry). Main outcome measuresIncident CRC (overall and site-specific). ResultsAmong men, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95%-confidence interval (CI)=1.08, 1.38) times higher CRC odds (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95%-CI=0.97, 1.22) times higher CRC odds. Higher WHR was more strongly associated with CRC risk among women (IVW-OR=1.25, 95%-CI=1.08, 1.43 per 0.07-ratio) than men (IVW-OR=1.05, 95%-CI=0.81, 1.36 per 0.07-ratio). BMI or WHR was associated with 104 metabolites (false-discovery-rate-corrected P[≤]0.05) including low-density lipoprotein (LDL) cholesterol, but these metabolites were generally unassociated with CRC in directions consistent with mediation of adiposity-CRC relations. In multivariable MR, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes - e.g. the univariable IVW-OR of BMI for CRC was 1.12 (95%-CI=1.00, 1.26), and 1.11 (95%-CI=0.99, 1.26) adjusting for LDL lipids. Conclusions and relevanceOur results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these alterations explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify mechanistic pathways.

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