Associations of plasma protein levels with risk of colorectal cancer: a proteome-wide Mendelian randomization study

Background The treatment of advanced or metastatic colorectal cancer (CRC) poses a global challenge. Mendelian Randomization (MR) has been primarily applied for repurposing licensed drugs and uncovering new therapeutic targets. Objective This study aims to systematically identify potential plasma protein targets for CRC using proteome-wide Mendelian randomization and evaluate their safety through phenome-wide association studies. Methods We conducted a comprehensive proteome-wide MR study to assess the causal relationships between plasma proteins and the risk of CRC. The plasma proteins were sourced from the Finland and Iceland decode database, encompassing GWAS data for plasma proteins (Olink-619 samples across 2925 proteins, SomaScan − 828 samples across 7596 proteins and Iceland decode database across 4907 proteins). Additionally, GWAS data for CRC were extracted from the UK Biobank-SAIGE database, including 3051 cases and 382,756 controls. Subsequently, colocalization analysis was performed to identify shared causal variants between plasma proteins and CRC. Finally, a phenome-wide association study (Phe-WAS) was conducted to examine the potential adverse effects of druggable proteins for CRC, utilizing the extensive UK Biobank-SAIGE database, encompassing 783 phenotypes. Results The MR analysis identified GREM1, DKKL1, and CHRDL2 as plasma proteins whose genetically predicted levels were positively associated with CRC risk, whereas TMEM132A exhibited an inverse association with CRC risk ( P_ fdr < 0.05). The colocalization analysis identified these four proteins as shared variation with CRC (PPH3 + PPH4 > 0.7), suggesting that these proteins represent potential direct targets for CRC intervention. Further phenotype-wide association studies showed no significant potential side effects of these targets ( P _fdr > 0.05). Conclusion This proteome-wide Mendelian randomization study offers a comprehensive molecular landscape of CRC, identifying GREM1, DKKL1, CHRDL2, and TMEM132A as potential therapeutic targets. Our research provides a critical foundation for future experimental validation and therapeutic development in colorectal cancer management.