Transcriptome- and Epigenome-Wide Association Studies of Tic Spectrum Disorder in Discordant Monozygotic Twins
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Tic spectrum disorder (TSD), including Tourette syndrome and chronic tic disorder, is a childhood-onset neurodevelopmental condition with complex genetic and environmental contributions. To investigate environmentally driven mechanisms, we analyzed peripheral blood from eleven monozygotic twin pairs either discordant or concordant for TSD using RNA sequencing and DNA methylation analysis. Differential expression analysis identified a dozen differentially expressed genes between TSD and non TSD individuals, most of which were long non-coding RNAs or pseudogenes. Expression of the small RNA gene RNY1 was significantly associated with tic severity, suggesting involvement of immune-related processes. DNA methylation (DNAm) analysis revealed no genome-wide significant loci but ~30,000 probes with p < 0.05 before multiple testing correction. Expression quantitative trait methylation (eQTM) analysis identified 236 methylation-associated genes. Gene set enrichment analysis demonstrated broad downregulation in TSD individuals of pathways related to translation, RNA processing, and neurobiological functions, with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including ribosome, nucleocytoplasmic transport, pluripotency signaling, and nicotine addiction. These results suggest that environmentally influenced epigenetic regulation contributes to TSD pathogenesis through repression of gene expression and dysregulation of immune and neuronal pathways. Despite a small sample size, the monozygotic twin design provides strong control for genetic background and identifies significant differences that contribute to the understanding of the underlying molecular mechanisms of TSD.