Background Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods To improve statistical power and interpretation for gene‐environment interaction (G?×?E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26?017 cases and 20?692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G?×?E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G?×?E effects (random effects). G?×?BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR 0.2. Results Among 4839 genes tested, genetically predicted expressions of FOXA1 (P?=?3.15?×?10?5), PSMC5 (P?=?4.51?×?10?4) and CD33 (P?=?2.71?×?10?4) modified the association of BMI on CRC risk for men; KIAA0753 (P?=?2.29?×?10?5) and SCN1B (P?=?2.76?×?10?4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P?=?2.31?×?10?5). Conclusions Aggregating G?×?E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.
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