TWAS of Cannabis Use Disorder and Anxiety GWAS Signals Against Ageing Gene Sets: Mechanistic Divergence and Translational Implications

Psychiatric disorders overlap with several biological systems that are also involved in ageing, but it remains unclear whether different psychiatric liabilities engage the same ageing-related molecular programmes. We compared cannabis use disorder (CUD) and anxiety disorders using transcriptome-wide association study (TWAS) results derived from large GWAS summary statistics and curated ageing-related gene sets. The analysis focused on NAD and sirtuin biology, senescence, apoptosis, AMPK/mTOR signalling, GLP1 and insulin pathways, glutamatergic plasticity, synapse pruning, complement, inflammation, and glial cell-type signatures. CUD and anxiety showed partial convergence on glial and metabolic ageing architecture, especially adult oligodendrocyte genes. The strongest divergence appeared in synapse-pruning genes: CUD loaded positively on TREM2 and negatively on SARM1, whereas anxiety showed the opposite pattern. Anxiety was more strongly associated with inflammatory response, TNF-NFκB signalling, cytokine signalling, intrinsic apoptosis, complement-related pruning, and NAD-linked axonal stress. CUD showed stronger enrichment in nucleus accumbens glutamatergic and long-term potentiation genes, CAMKK–AMPK energy sensing, GLP1/insulin secretion, KATP-linked excitability, and SIRT6/SIRT1-related ageing regulation. NAD and senescence findings were not uniform; instead, they suggested branch-specific redistribution across phenotypes. These findings support a model in which anxiety reflects an inflammatory-apoptotic and axonal-stress ageing profile, whereas CUD reflects reward-plasticity and metabolic-remodelling biology. The TREM2/SARM1 axis, together with inflammation/apoptosis, AMPK/GLP1, NAD/sirtuin, and oligodendrocyte pathway scores, may help guide future stratification studies.Keywords: TWAS, cannabis use disorder, anxiety disorders, ageing, NAD, senescence, microglia, synapse pruning, precision psychiatry