A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator

Abstract Adiposity is an established risk factor for colorectal cancer (CRC). However, the pathways underlying this relationship, and specifically the role of the circulating proteome, is unclear. Utilizing two-sample Mendelian randomization and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable (UV) associations between: (I) adiposity measures (body mass index, BMI; waist hip ratio, WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (II) adiposity measures and plasma proteins, and (III) adiposity-associated plasma proteins and CRC risk. We used multivariable MR (MVMR) to investigate the potential mediating role of adiposity- and CRC-related proteins in the adiposity-CRC association. BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumour site. 6,591 adiposity-protein (2,628 unique proteins) and 33 protein-CRC (8 unique proteins) associations were identified using UVMR and colocalization. 1 protein, GREM1 was associated with BMI only and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated - suggestive of a potential mediating role - most strongly for the BMI-overall CRC association in women. These results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from cis -SNP UVMR and colocalization analyses, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women, and warrants further experimental investigation.