Identifying metabolic features of colorectal cancer liability using Mendelian randomization

Abstract

Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. To investigate whether changes in circulating metabolites characterise the early stages of colorectal cancer (CRC) development, we examined associations between a genetic risk score (GRS) associated with CRC liability (72 single nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N=6,221). Linear regression models were applied to examine associations between genetic liability to colorectal cancer and circulating metabolites measured in the same individuals at age 8, 16, 18 and 25 years. The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P<0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N=118,466, median age 58y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism, and suggest that fatty acids may play an important role in CRC development.

The association between body mass index and metabolite response to a liquid mixed meal challenge: a Mendelian randomization study

“…Previous cross-sectional, Mendelian randomization (MR), recall-by-genotype, and randomized controlled trials have established both observational and causal associations between BMI and fasted metabolite and protein abundances [ 15 , [24] , [25] , [26] ]. Such studies have informed and motivated downstream studies aimed at elucidating the causal effects of BMI-driven metabolite variation on disease outcomes, such as colorectal cancer [ 27 , 28 ].…”