Association of antipsychotic drug target genes and risk of lung cancer: a Mendelian randomization study.

BACKGROUND: Antipsychotic drugs are associated with various tumors, but their causal relationship with lung cancer risk remains unclear. We aimed to investigate this association using Mendelian randomization (MR) analyses. METHODS: We performed summary-data-based MR (SMR) using blood-derived expression quantitative trait loci (eQTL) and two sample-MR using single nucleotide polymorphism (SNP) of antipsychotic drug target genes. Colocalization analysis was performed with cis-eQTLs, and sensitivity analyses included the Heterogeneity in dependent instruments (HEIDI) test and Multi-SNP-based SMR. RESULTS: SMR showed that higher DRD4 expression was associated with lower lung cancer risk (PSMR = 0.009; PHEIDI >0.01; PSMR_multi = 0.0338). Two-sample MR further indicated inverse associations for KCNH2 (OR: 0.91; 95%CI: 0.83-0.99; P = 0.040) and DRD4 (OR: 0.89; 95%CI: 0.79-0.99; P = 0.040) with lung cancer risk. Additionally, elevated HTR6 and DRD4 expression was linked to decreased lung adenocarcinoma (LUAD) risk (HTR6, OR: 0.89; 95%CI: 0.81-0.99; P = 0.014; DRD4, OR: 0.87; 95%CI: 0.76-0.98; P = 0.016). Colocalization analyses did not support shared causal variants (PP.H4 < 0.8). CONCLUSION: These findings provide insights into the potential oncologic implications of antipsychotic drug use and may inform clinical management.