Causal Associations Between Smoking, Brain Structural Alterations and Psychiatric Disorders: Evidence From a Mediation Analysis

Both epidemiological and Mendelian randomization (MR) studies have confirmed the association between smoking and psychiatric disorders, yet the underlying mechanism remains poorly understood. To address this gap, this study aimed to evaluate causal relationships between smoking, brain structural alterations, and psychiatric disorders and to identify genetic and neuroimaging mediators. We analysed summary data from the genome-wide association study (GWAS) and multimodal neuroimaging data, using linkage disequilibrium score regression (LDSC) to quantify genetic correlations and two-sample bidirectional MR to assess causality between smoking and three psychiatric disorders: schizophrenia (SCZ), major depressive disorder (MDD) and bipolar disorder (BD). Additionally, we conducted mediation analysis to identify brain structural mediators and colocalization and pathway analyses to elucidate shared genetic architecture. LDSC analysis revealed significant genetic correlations between smoking and MDD (r_g = 0.41), SCZ (r_g = 0.16) and BD (r_g = 0.15). Consistently, bidirectional MR confirmed a bidirectional causal relationship between smoking and SCZ/MDD and a unidirectional causal effect of smoking on BD. Mediation analysis further revealed that microstructural disorganization in the left uncinate fasciculus mediated 19.6% (95% CI: 3.36%-35.8%) of the effect of smoking on MDD risk. Moreover, colocalization analysis implicated SH2B2 as a pleiotropic locus linking UF orientation dispersion (OD) to prefrontal-amygdala gene expression, suggesting that smoking may exacerbate corticolimbic dysfunction by inducing SH2B2 hypermethylation. Taken together, our findings establish smoking as a causal risk factor for SCZ, MDD and BD, with corticolimbic white matter degeneration serving as a key mediator, and they highlight the SH2B2-TrkB axis as a mechanistic conduit for genetic and environmental risk, pointing to therapeutic targets to disrupt smoking related psychiatric disorders.