Neurostructural alterations, trait impulsivity, and genetic architecture in individuals with methamphetamine dependence: a multimodal imaging-genetics study.

Methamphetamine use disorder (MUD) represents a substantial global health challenge, largely attributable to the absence of effective treatments stemming from limited understanding of its neurobiological mechanisms. This study aimed to investigate the structural brain alterations, trait impulsivity, and genetic factors underlying MUD. We conducted structural magnetic resonance imaging scanning and whole-exome sequencing on a cohort of 142 male participants (91 patients with MUD vs. 51 healthy controls). Voxel-based morphometry revealed a significant reduction in gray matter volume (GMV) in the left thalamus among MUD patients, which exhibited a negative correlation with motor impulsivity (MI). Mediation analysis further demonstrated that MI mediated the relationships between thalamic GMV, duration of drug use, and MUD severity. Gene- and gene set-based burden tests identified 72 genes and three biological pathways: Cytidine Analogs Cytotoxicity, Muscle Structure Development, and Nuclear Speck, that were significantly associated with thalamic volume. GO enrichment analyses of 362 common genetic variants indicated a significant involvement in ciliary and microtubule-based motility processes. Concurrently, KEGG pathway analyses highlighted cytoskeletal and extracellular matrix signaling pathways. Gene-environment interaction analyses revealed that thalamic volume was significantly influenced by the interaction between rs12729569 and METH use, as well as between rs2282440 and duration of use. These findings suggest the thalamus as a critical structural substrate that links impulse control with METH-related neurotoxicity, emphasizing the role of cytoskeletal dynamics and ciliary function. Genetic variants that influence thalamic vulnerability may serve as promising biomarkers for risk stratification and the development of personalized interventions in MUD.