Opposing Ageing-Related Transcriptomic Profiles Distinguish Opioid Exposure Liability from Dependence Liability

Opioid use disorder (OUD) involves separable stages of exposure and dependence, but many genetic studies have treated these liabilities as a single phenotype. In this study, transcriptome-wide association study (TWAS) methods were applied to the Psychiatric Genomics Consortium Substance Use Disorders 2020 opioid meta-analysis summary statistics to examine ageing-related gene pathways across brain tissues. Genetic liability for opioid exposure was strongly associated with reduced predicted expression of complement components and synaptic-pruning genes, together with negative signals in astrocyte and senescence-related gene sets. By contrast, liability for dependence among opioid-exposed individuals showed positive enrichment in AMPK–mTOR nutrient-sensing pathways, mitochondrial oxidative phosphorylation, especially DLD, and selected NAD/sirtuin pathways, accompanied by presynaptic and DNA-repair adaptations. Many ageing-related gene sets showed opposing directional profiles between exposure and dependence contrasts, indicating that these stages engage partially antagonistic transcriptomic programs. Gene-level analyses identified influential drivers and directional sign-flips, including CASP7, TERF2, STX1A, and ADCY6, which further supported the stage-specific pattern. These findings suggest that opioid exposure and opioid dependence are biologically distinguishable at the level of ageing-related brain gene expression. The results nominate stage-specific risk modules and biomarker hypotheses that may inform future precision approaches to OUD prevention and treatment.