Transcriptomic Ageing Pathways in Alcohol Misuse and Anxiety: Senescence-Like Striatal Stress Programs and Anxiety-Linked Inflammatory-Apoptotic Signatures

Alcohol misuse is genetically and clinically heterogeneous. Standard genome-wide association studies have helped define common genetic liability, but they may obscure subtype-specific biology. Ageing-related processes, including cellular senescence, mitochondrial dysfunction, NAD metabolism, apoptosis, and neuroimmune signaling, are increasingly relevant to psychiatric disease, yet they have not been systematically examined in genetically stratified alcohol-misuse subgroups or in cross-disorder comparisons with anxiety. We performed a transcriptome-wide association study gene-set analysis of curated ageing-related pathways using genetically predicted expression associations from alcohol-misuse subgroup GWAS contrasts and a large anxiety-disorder GWAS.The strongest alcohol-misuse signal was enrichment of cellular senescence and senescence-regulation gene sets in contrasts involving subgroup 2 versus subgroups 3 and 4. This effect was most apparent in caudate, with reported Stouffer Z values around 3.9 to 4.1 in tissue-specific analyses and an overall Z up to 5.98 for the 2v3 contrast with permutation support. Gene-level results highlighted YPEL3, SIRT6, WRN, TP53, CDKN-family genes, ATM, and telomere-maintenance genes. Anxiety showed a different dominant profile, with strong intrinsic apoptosis enrichment, cytokine and TNFA–NFKB signaling, and positive NAD/nicotinate metabolism signals. Key anxiety-associated drivers included BAK1, BAD, BCL2L1, TNF, NFKB1, RELA, TLR4, NAMPT, SIRT3, and SIRT5. Cross-disorder analyses suggested anxiety-dominant cytokine and NAD effects, shared immune/HLA/complement profile proximity, and contrast-dependent BCL-2 family alignment or opposition between alcohol-misuse contrasts and anxiety.These findings support a cautious model in which alcohol-misuse genetic subtypes differ in striatal senescence-like stress adaptation, mitochondrial and AMPK/mTOR energy sensing, and synaptic plasticity, whereas anxiety shows a stronger apoptosis-inflammatory-NAD compensation profile. The results do not demonstrate cellular senescence or apoptosis in vivo. They do, however, offer a basis for replication, colocalization, biomarker work, and pathway-score-based stratification in precision psychiatry.Keywords: alcohol misuse, alcohol use disorder, anxiety, TWAS, ageing, cellular senescence, NAD, apoptosis, neuroinflammation, caudate, precision psychiatryAlcohol misuse is genetically and clinically heterogeneous. Standard genome-wide association studies have helped define common genetic liability, but they may obscure subtype-specific biology. Ageing-related processes, including cellular senescence, mitochondrial dysfunction, NAD metabolism, apoptosis, and neuroimmune signaling, are increasingly relevant to psychiatric disease, yet they have not been systematically examined in genetically stratified alcohol-misuse subgroups or in cross-disorder comparisons with anxiety. We performed a transcriptome-wide association study gene-set analysis of curated ageing-related pathways using genetically predicted expression associations from alcohol-misuse subgroup GWAS contrasts and a large anxiety-disorder GWAS.The strongest alcohol-misuse signal was enrichment of cellular senescence and senescence-regulation gene sets in contrasts involving subgroup 2 versus subgroups 3 and 4. This effect was most apparent in caudate, with reported Stouffer Z values around 3.9 to 4.1 in tissue-specific analyses and an overall Z up to 5.98 for the 2v3 contrast with permutation support. Gene-level results highlighted YPEL3, SIRT6, WRN, TP53, CDKN-family genes, ATM, and telomere-maintenance genes. Anxiety showed a different dominant profile, with strong intrinsic apoptosis enrichment, cytokine and TNFA–NFKB signaling, and positive NAD/nicotinate metabolism signals. Key anxiety-associated drivers included BAK1, BAD, BCL2L1, TNF, NFKB1, RELA, TLR4, NAMPT, SIRT3, and SIRT5. Cross-disorder analyses suggested anxiety-dominant cytokine and NAD effects, shared immune/HLA/complement profile proximity, and contrast-dependent BCL-2 family alignment or opposition between alcohol-misuse contrasts and anxiety.These findings support a cautious model in which alcohol-misuse genetic subtypes differ in striatal senescence-like stress adaptation, mitochondrial and AMPK/mTOR energy sensing, and synaptic plasticity, whereas anxiety shows a stronger apoptosis-inflammatory-NAD compensation profile. The results do not demonstrate cellular senescence or apoptosis in vivo. They do, however, offer a basis for replication, colocalization, biomarker work, and pathway-score-based stratification in precision psychiatry.Keywords: alcohol misuse, alcohol use disorder, anxiety, TWAS, ageing, cellular senescence, NAD, apoptosis, neuroinflammation, caudate, precision psychiatry