Study design. First, linear regression models were used to examine the relationship between genetic susceptibility to adult colorectal cancer and circulating metabolites measured in ALSPAC participants at age 8, 16, 18 and 25 years. Next, we performed a reverse Mendelian randomization analysis to identify metabolites influenced by CRC susceptibility in an independent population of adults. Finally, we performed a conventional (forward) Mendelian randomization analysis of circulating metabolites on CRC to identify metabolites causally associated with CRC risk. Consistent evidence across all three methodological approaches was interpreted to indicate a causal role for a given metabolite in CRC aetiology.

Associations of genetic liability to adult colorectal cancer (based on a 72 SNP genetic risk score) with clinically validated metabolic traits at different early life stages among ALSPAC offspring (age 8y (N=4,767), 16y (N=2,930), 18y (N=2,613), and 25y (N=2,559)). Estimates shown are beta coefficients representing the SD difference in metabolic trait per doubling of genetic liability to colorectal cancer (purple, 8y; turquoise, 16y; red, 18y; black, 25y). Filled point estimates are those that pass a Benjamini–Hochberg FDR multiple-testing correction (FDR < 0.05).

Associations of genetic liability to colorectal cancer with clinically validated metabolic traits in an independent sample of adults (UK Biobank, N=118,466, median age 58y) based on reverse two sample Mendelian randomization analyses. Estimates shown are beta coefficients representing the SD-unit difference in metabolic trait per doubling of liability to colorectal cancer. Filled point estimates are those that pass a Benjamini–Hochberg FDR multiple-testing correction (FDR < 0.05).

Associations of clinically validated metabolites with colorectal cancer based on conventional (forward) two sample Mendelian randomization analyses in individuals from UK Biobank (N=118,466, median age 58y) . Estimates shown are beta coefficients representing the logOR for colorectal cancer per SD metabolite. Filled point estimates are those that pass a Benjamini–Hochberg FDR multiple-testing correction (FDR < 0.05).