Smoking as a mediator in the association between major depressive disorder and schizophrenia on lung cancer risk: a bidirectional/multivariable and mediation Mendelian randomization study.

Background & Aims: Major depressive disorder and schizophrenia have been hypothesized to be closely associated with cancer. However, the associations between these psychiatric conditions and the development of lung cancer remain uncertain. This study aimed to explore the causal relationship among major depressive disorder, schizophrenia, and the risk of lung cancer. Methods: Two-sample bidirectional/multivariable and mediation Mendelian randomization (MR) analyses were conducted. Genome-wide summary data on major depressive disorder (N=500,199) and schizophrenia (N=127,906) were utilized. Data on the risk of lung cancer (overall, adenocarcinoma, and squamous cell) were collected from a cohort of individuals of European ancestry (N=27,209). Three smoking-related behaviors (smoking initiation, pack years of smoking, and cigarettes smoked per day) were included in the multivariable and mediation MR analyses. Results: Patients with schizophrenia had a significantly greater risk of developing lung cancer (odds ratio (OR) = 1.144, 95% confidence interval (95% CI): 1.048-1.248, P = 0.003). The number of cigarettes smoked per day partially mediated the relationship between schizophrenia and the overall risk of lung cancer (OR = 1.185, 95% CI: 1.112-1.264, P = 0.021, proportion of mediation effect: 61.033%). However, there is no reliable evidence indicating an association between major depressive disorder and the risk of lung cancer (overall, adenocarcinoma, and squamous cell cancer). Conclusions: The findings indicated an association between schizophrenia and an increased risk of lung cancer, with smoking served as a partial mediator. When smoking was included in the regression analysis, the explanatory power of schizophrenia diagnosis was reduced, suggesting that smoking may be an important causal contributor to lung cancer in this population. Given the high prevalence of smoking among individuals with schizophrenia, these results underscore the need for further research to explore the underlying mechanisms of smoking's impact. Consequently, greater emphasis should be placed on monitoring the respiratory health of individuals with schizophrenia and implementing early interventions to address smoking-related behaviors.