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Depression, anxiety, and genetics shape smoking risk through salience networks
Matthew P Gunn1, Gregory M Rose2, Alexis E Whitton3
1Department of Psychiatry, University of Illinois at Chicago, Chicago IL USA.
Background:
Smoking trajectories in young adults vary, with some light smokers escalating to dependence while others reduce or quit. Depressive and anxious traits relate to altered large-scale network connectivity, including the salience network (SN). Dopaminergic (DRD2 Taq1A) and serotonergic (5-HTTLPR) variants may further shape these trajectories, but trait-gene links to neural circuits and nicotine sensitivity remain unclear.
Methods:
Sixty-eight young light smokers (18-24) completed nicotine and placebo sessions. Resting-state fMRI assessed functional connectivity; reward sensitivity was measured with the Probabilistic Reward Task. Depressive/anxious traits and DRD2/5-HTTLPR genotypes were obtained, and smoking progression was tracked.
Results:
Depressive traits predicted weaker SN connectivity (insula-ACC; insula-dlPFC) but stronger insula-sgACC coupling. Anxious traits predicted weaker precentral-insula/dlPFC connectivity and stronger precentral-temporal-sgACC connectivity. Higher depressive traits combined with nicotine-enhanced reward sensitivity (NERS) predicted reduced prefrontal-limbic connectivity, whereas depression with smoking progression predicted increased insula-striatal-hippocampal connectivity. Gene × trait interactions suggested distinct endophenotypes: Depression × DRD2 predicted sgACC-insula and hippocampus-ACC connectivity; Anxiety × 5-HTTLPR predicted ACC-PCC and hippocampus-dlPFC connectivity.
Conclusions:
The sgACC within the SN may act as a convergence hub linking affective traits, genetic risk, and nicotine sensitivity: depression-related risk reflects hypo-salience/reward deficiency, whereas anxiety-related risk reflects hyper-salience/vigilance.
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