Integrated multi‐layer transcriptomics reveals a gamma‐aminobutyric acid‐centred molecular state in Tourette syndrome
Qingsong Zhao, Fathallah Yasmine, Yanan Peng, Le Liu, Juan Wang, Qian Wang, Jing Tan, Ran Hua, De WuAbstract
Aims
Gamma‐aminobutyric acid (GABA)ergic dysfunction is central to Tourette syndrome (TS), yet evidence linking peripheral signals, upstream regulation, pharmacologic response and striatal cellular context remains fragmented. We investigated whether a GABA‐defined peripheral molecular state in TS could be linked to candidate regulatory signals, pharmacologic response, striatal cell‐type localisation, and local communication networks.
Methods
We integrated peripheral blood mRNA (GSE30470), serum miRNA profiles (GSE146509), chronic diazepam brain transcriptomes (GSE76700) and striatal single‐cell RNA‐seq (GSE116470). TS samples were stratified by a GABA_index derived from GABA‐related gene expression. Analyses included differential expression, miRNA target enrichment, disease‐drug reversal, cell‐type localisation, and ligand‐receptor communication.
Results
GABA_index stratification separated TS into GABA_Low and GABA_High states, revealing 1290 differentially expressed genes. The only high‐confidence serum miRNA was hsa‐miR‐483‐3p; enrichment of its validated targets in neurotrophin, Ras, Rap1, axon guidance and cAMP pathways indicates upstream cortico‐striato‐thalamo‐cortical (CSTC) regulation. Chronic diazepam reversed the TS transcriptional signature in cortex, negatively enriching TS_Up and positively enriching TS_Down genes. Single‐cell analysis localised GABA/CSTC programs to medium spiny neurons and interneurons; communication analysis revealed an extracellular matrix/adhesion‐centred striatal microenvironment with fibroblast and vascular leptomeningeal cell contributions.
Conclusion
TS is associated with a peripheral GABA‐centric molecular state linked to upstream miRNA regulation and striatal neuronal microenvironments.