Shared genetic architecture of psychoactive substance use and pan-cancer: insights from a large‑scale genome‑wide cross‑trait analysis

BACKGROUND: Psychoactive substance use (PSU) and cancer are frequently observed comorbidities that have reciprocal influences and shared behavioral traits of the affected patients. While, e.g., nicotine and alcohol are major carcinogens in the etiology of lung and head and neck cancers, little is known about a shared overarching genetic architecture of PSU and cancer that may predispose individuals to both illnesses. METHODS: Large-scale genome-wide association study (GWAS) summary data revealed shared genetic architecture between cancer and PSU, including alcohol use dependence (AlcUD) and nicotine use dependence (NicUD). Genetic correlations between PSU and cancer were assessed by linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Mendelian randomization (MR) analysis was additionally employed to explore causal associations between PSU and cancer. Moreover, phenome-wide association study (PheWAS) and drug target analysis were utilized to evaluate the safety and therapeutic value of pleiotropic hub genes. RESULTS: GWAS-based cross-referencing of PSU and cancer identified 34 shared trait pairs with significant genetic correlations and a total of 97 pleiotropic genomic risk loci. Affected loci mapped to genes expressed in the brain cerebellum (n = 109) and included cross-trait pleiotropic hub genes (n = 21). MR analysis further identified causal effects of AlcUD and NicUD on cancer risk. After exclusion of genes at high risk of side effects upon inhibition in a PheWAS, cholinergic receptor nicotinic alpha 2 (CHRNA2), histamine receptor H3 (HRH3), and protein tyrosine kinase 6 (PTK6) were identified as potentially druggable targets. CONCLUSIONS: In summary, we identified a shared genetic architecture comprising pleiotropic cerebellar hub genes linking PSU-cancer trait pairs and described potential interventional drugs.