Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for cutaneous melanoma

Background: Cutaneous melanoma (CM) is the deadliest form of skin cancer. Mendelian randomization (MR) and local analysis have been widely used in the search for therapeutic targets for diseases. Methods: Plasma proteins data were obtained from the UK Biobank Pharmaceutical Proteomics Project (UKB-PPP) database. The GWAS data for CM were extracted from the Finnish (R10) database. Proteome-wide MR analysis to assess the causal relationship between plasma proteins and CM. Colocalization analysis was used to identify causal variants shared between plasma proteins and CM. A phenotype-wide association study (PheWAS) was used to assess the potential adverse effects of proteins that could treat CM on 2480 phenotypes in the Finnish (R10) database. Results: MR analysis revealed that 5,6-hydroxyindole-2-carboxylate oxidase (TYRP1) (OR: 0.23, 95% CI: 0.12-0.44) and dipeptidase 1(DPEP1) (OR: 0.63, 95% CI: 0.12-0.44) were associated with CM. The evidence from the colocalization analysis supported an inverse association between DPEP1 levels and the risk of CM, but the evidence from the colocalization analysis of TYRP1 was low grade. PheWAS suggested that DPEP1 as a therapeutic target for CM may cause dementia. Conclusions: Our investigation examined the causal relationships between two plasma proteins and CM, providing a comprehensive understanding of potential therapeutic targets.