ABSTRACT: Tic disorders and Tourette syndrome are neurodevelopmental disorders arising from interplay between genetic and environmental factors. Gene regulation, via chromatin and other epigenetic mechanisms, may provide a key link between gene-environment interactions, yet remains under-investigated in tic disorders. We performed bulk RNA sequencing of peripheral blood from 28 children with tic disorders (19 with Tourette syndrome, aged 6-16, median age 10 years, 18 (64%) males) compared to 20 matched healthy controls (aged 1-25, median age 11 years, 13 (65%) males). Differentially expressed genes (DEGs) were identified following false discovery rate (FDR) correction, and pathway enrichment was analysed using Gene Set Enrichment Analysis (GSEA) based on Gene Ontology (GO) and Reactome databases. To assess convergence between peripheral and brain molecular changes, DEGs were compared with published post-mortem brain transcriptomic data from individuals with Tourette syndrome. A total of 4,169 DEGs (FDR < 0.05) were identified in blood transcriptomic analysis, with 2,192 upregulated and 1,977 downregulated genes. The blood transcriptomic findings included upregulation of chromatin- and cohesin-related pathways, immune activation, and cell signalling, and downregulation of translational machinery, mitochondrial function, and DNA methylation. Comparison with post-mortem brain transcriptomic data revealed 30 overlapping genes, including 20 that were concordantly upregulated in both blood and brain, predominantly associated with immune, signalling, and cellular stress responses. Our data points to gene regulation and chromatin biology as a nexus where genetic risk and environmental exposures converge in tic disorders and related neurodevelopmental disorders, and highlight epigenetic and immune-targeting therapies as promising avenues for disease modification.
