BACKGROUND: Colorectal cancer (CRC) is the most common malignant tumor of the digestive tract worldwide, however, the potential targets for CRC and its subsites (colon cancer & rectum cancer) are less known. The aim of this study is to explore potential therapeutic targets for CRC. METHODS: A proteome-wide genome-wide association studies (GWAS) in 35,559 Icelanders with 4,907 plasma proteins was used as instrumental variables (P value <
5×10 RESULTS: A total of 31 proteins were found to be in robust causal associations with CRC and the proteins' effects displayed anatomic site-specificity in MR analysis. The subsequent colocalization analysis pinpointed that CHDRL2 had a shared region with CRC and its two subsites, suggesting the importance of targeting it. Besides, IGF2R and ENPEP displayed anatomic site-specificity to colon cancer while ASRGL1 was strongly correlated only with the risk of rectal cancer. Enrichment analysis revealed functions of these proteins in CRC, and DrugBank showed their target drug. CONCLUSIONS: In summary, our study has identified a common protein, CHDRL2, as the drug targets for CRC and its subsites. Besides, IGF2R and ENPEP displayed anatomic site-specificity to colon cancer while ASRGL1 was strongly correlated only with the risk of rectal cancer.