Identifying potential drug targets for seborrheic keratosis through druggable genome-wide Mendelian randomization and colocalization analysis

Seborrheic keratosis (SK) is the most prevalent benign epidermal tumor in adults, characterized by complex pathogenesis and diverse clinical subtypes. This study systematically evaluated the genetic susceptibility and identified novel therapeutic targets for SK. We applied two-sample Mendelian randomization (MR) using cis-eQTL data for druggable genes in blood and SK genome-wide association study (GWAS) data to identify causal genes. Sensitivity and colocalization analyses were performed to assess MR reliability and estimate the likelihood of shared causal variants between cis-eQTLs of druggable genes and SK. For additional validation, we conducted enrichment analysis, phenome-wide association analysis, and candidate drug prediction to further interpret our findings. The expression levels of 18 druggable genes were significantly associated with SK susceptibility (adjusted p-value [FDR] < 0.05), of which 8 were identified as risk factors for SK, while 10 significantly reduced SK predisposition. The susceptibility of SK was likely linked to a shared causal variant with two significant druggable genes, CASP8 (OR = 0.725, 95%CI: 0.622-0.844, PPH4 = 0.907) and TSSK6 (OR = 0.478, 95%CI: 0.327-0.696, PPH4 = 0.970). Functional analyses revealed CASP8 and TSSK6 may influence SK onset and progression through mechanisms cell differentiation and programmed apoptosis regulation. CASP8 and TSSK6 stand out as the most promising potential drug targets for reducing the susceptibility of SK. Our findings identify potential drug targets and provide valuable insights for future SK drug development.