Polycomb Epigenetic Programs Contribute to Tic Disorder Pathophysiology Independently of Antipsychotic Drug Targets

Tic disorders are developmental neuropsychiatric conditions in which involuntary motor and vocal tics are thought to arise from abnormal cortico-striato-thalamo-cortical and related cerebellar-thalamo-cortical circuit function. Current treatments, especially dopamine-modulating antipsychotics, can reduce tic severity but are often limited by incomplete response, adverse effects, and uncertain disease-modifying value. Large-scale genetic studies have implicated neurodevelopmental and synaptic biology in tic liability, but the mechanistic convergence of these signals remains incompletely defined. Here, we tested whether tic-associated genetically regulated expression signals from S-PrediXcan/TWAS meta-Z scores based on the Yu et al. tic-disorder GWAS were enriched in Polycomb/H3K27me3-linked neuronal identity and synaptic maintenance programs derived from Cheung’s 2026 aging-neuron analysis, compared with an antipsychotic drug-target comparator set. Sixteen Polycomb-mapped KEGG pathways were evaluated using GSEA-style enrichment, signed and absolute ranking, leading-edge analysis, directionality testing, removal of antipsychotic-related genes, functional enrichment, brain-tissue profiling, and DGIdb drug-gene ranking. Five Polycomb pathway sets showed nominal enrichment against the antipsychotic comparator: RNA polymerase, spliceosome, adherens junction, long-term potentiation, and glutamatergic synapse. Four remained significant and stronger than the comparator after antipsychotic-gene removal: RNA polymerase, spliceosome, adherens junction, and long-term potentiation. The antipsychotic set, but not the Polycomb sets, showed significant negative directional skew. Leading genes included EP300, RHOA, POLR2I, CNTF, ABCB9, GRM3, PRPF19, CD40, LPCAT3, PTPN6, ABCB1, PAK4, NCK2, and CREB3L4. Functional enrichment emphasized actin cytoskeleton regulation, axon guidance, synaptic signaling, spliceosome, adherens junction, and long-term potentiation. Tissue-level signals mapped to hippocampus, amygdala, nucleus accumbens, caudate, frontal cortex, and anterior cingulate cortex. These findings support an independent Polycomb-linked component of tic genetic liability involving neuronal adhesion, synaptic plasticity, and transcriptional/RNA-processing fidelity. They provide a mechanistic rationale for why antipsychotics may be useful yet insufficient, and they nominate EP300, RHOA-related cytoskeletal signaling, PRPF19/SF3B spliceosome components, and long-term potentiation machinery as validation targets for mechanism-based stratification and augmentation strategies.