Project description:Inattention, impulsivity and hyperactivity are the primary behaviors associated with Attention Deficit / Hyperactivity Disorder (ADHD). Previous studies proved that peripheral blood gene expression signature could mirror central nervous system disease. This study determined if gene expression in blood correlated with inattention, hyperactivity/impulsivity rating scales and/or both in subjects with Tourette syndrome (TS).
Project description:We performed the first single-nucleus transcriptomic analysis of postmortem DLPFC tissue from individuals with TD and age-matched neurotypical controls. No significant differences in cell numbers were observed between groups. Gene ontology analyses revealed broad upregulation of transcripts related to protein synthesis, most prominently in microglia, oligodendrocytes, and interneurons. Within neuronal clusters, these changes were most pronounced in superficial and middle-layer pyramidal neurons and vasointestinal peptide (VIP)-positive interneurons. Differential expression analyses showed widespread increases in immediate early genes (IEGs) and glucocorticoid-responsive transcripts across all cell types in TD. Furthermore, all cell populations in TD samples exhibited enrichment for genes associated with stress-related psychopathology. These findings implicate the DLPFC as a locus of heightened stress responsivity and disrupted excitatory–inhibitory development in TD.
Project description: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.