Bidirectional genetic and phenotypic links between smoking and striatal iron content involving dopaminergic and inflammatory pathways.

Tobacco smoking is a major risk factor for cardiovascular and lung diseases. A better understanding of its neurobiological underpinnings will benefit the prevention of smoking-related illnesses and mortality. Previous studies link smoking to increased iron concentration in the striatum, a central component of the brain's reward system, and to reduced cognitive performance. This study aimed to investigate whether smoking and striatal iron share common biological pathways and to assess potential causal relationships between the two. Using data from the UK Biobank, we investigated phenotypic and genetic correlations, and causal relationships between smoking initiation and magnetic resonance imaging (MRI)-derived markers of iron content (T2* and quantitative susceptibility mapping) in the bilateral putamen, caudate and accumbens nuclei. We found positive correlations between smoking and striatal iron (β ∈ [0.03, 0.40], P < 0.001), particularly when comparing current smokers with never smokers. Striatal iron was positively associated with pack-years (β ∈ [0.11, 0.13], P < 0.001) and inversely related to years since smoking cessation (β ∈ [0.06, 0.10], P < 0.001), suggesting iron levels may decrease after quitting. Genetic analysis confirmed phenotypic correlations, with shared genetic associations (P < 2.73 × 10-6, or 0.01 for candidate genes) in genes related to dopaminergic, glutamatergic and synaptic systems (DRD2, PPP1R1B, NCAM1, DLX5, GGACT, NAT16, PLEKHM1). Causality analysis revealed a relationship from smoking to striatal iron via genes involved in synaptogenesis and plasticity (BAI3, SEMA6D, TENM2), with evidence of reverse causality from iron to smoking through inflammatory and immune system-related genes (ING5, NLRP7). There appear to be links between smoking and striatal iron with complex causal mechanisms involving synaptic transmission and inflammatory circuits. Striatal iron content could serve as a biomarker for smoking-related neurobiological changes and a potential target for interventions aimed at mitigating cognitive decline related to striatal iron accumulation.