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

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.

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.

SMR showed that higher DRD4 expression was associated with lower lung cancer risk (P_SMR = 0.009; P_HEIDI >0.01; P_SMR_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).

These findings provide insights into the potential oncologic implications of antipsychotic drug use and may inform clinical management.