Cross-Disorder Pruning-Plasticity-Aging Architecture in Substance Use Disorders and Anxiety: Transcriptome-Wide Association Insights and Mechanistic Synthesis.

Authors

Ngo Cheung

Published in

Cureus. Volume 18. Issue 6. Pages e110806. Epub Jun 13, 2026.

Abstract

Substance use disorders and anxiety are clinically heterogeneous, and broad case-control genetic designs can obscure stage- and subtype-specific biology. A recent series of five transcriptome-wide association study (TWAS) preprints by Cheung examined opioid exposure versus dependence progression, alcohol misuse latent classes, cannabis use disorder, anxiety, and aging-related gene sets. Together, these studies suggest a cross-disorder architecture organized around a Pruning-Plasticity-Aging axis. This synthesis is narrative and hypothesis-generating, because the primary cross-disorder evidence comes from preprints and genetically predicted expression rather than measured patient expression. In this model, liability is not distributed along a single psychiatric-risk continuum. Instead, opioid exposure and some lower-risk or internalizing alcohol profiles appear to involve altered neuroimmune pruning and glial-synaptic refinement, whereas opioid dependence progression, heavier alcohol classes, broad-risk alcohol profiles, and cannabis use disorder show stronger involvement of glutamatergic plasticity, presynaptic adaptation, reward-circuit remodeling, AMP-activated protein kinase-mechanistic target of rapamycin (AMPK-mTOR) nutrient sensing, mitochondrial bioenergetics, and selected nicotinamide adenine dinucleotide (NAD)/sirtuin stress-response branches. Anxiety diverges by loading more strongly on inflammatory-apoptotic signaling, complement/sterile alpha and toll/interleukin receptor motif-containing protein 1 (SARM1)-linked axonal stress, and mitochondrial NAD-stress programmes. The most promising findings include stage-specific opposition in opioid TWAS profiles, latent-class plasticity inversion in alcohol misuse, a triggering receptor expressed on myeloid cells 2 (TREM2)-positive cannabis use disorder profile contrasted with a SARM1/complement C1q C chain (C1QC)-positive anxiety profile, and branch-specific rather than global aging biology. This review synthesizes these findings; places them in established addiction, neuroimmune, and aging biology; and outlines validation priorities for colocalization, fine-mapping, cell-type resolution, and functional testing.

PMID:
42299234
Bibliographic data and abstract were imported from PubMed on 16 Jun 2026.

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