Identifying potential drug targets for tourette syndrome: a Mendelian randomization study based on druggable genes

Tourette syndrome (TS) is a chronic neurodevelopmental disorder with childhood onset characterized by multiple motor tics and at least one vocal tic, with symptoms persisting for over one year. Its exact etiology remains unclear. Identifying novel therapeutic targets for TS is critically important. We utilized cis-expression quantitative trait loci (cis-eQTLs) of druggable genes obtained from the eQTLGen Consortium and genome-wide association study (GWAS) data for TS from the Psychiatric Genomics Consortium as the outcome to simulate the effects of pharmacological interventions on TS via Mendelian randomization (MR). Colocalization analyses were then conducted to validate the findings. To further corroborate these results, we investigated the role of DNA methylation in mediating the relationship between druggable gene expression and TS. The expression of seven druggable genes was significantly associated with TS susceptibility (FDR < 0.05). TS susceptibility and three key genes (RET, CAPNS1, and LAMA5) were likely to share a causal variant. Further DNA methylation analysis identified seven critical methylation sites (cg02605258, cg02907768, cg06026331, cg09831553, cg12382846, cg19674797, and cg20752878), which indirectly influence TS development by regulating LAMA5 gene expression. LAMA5 is the most promising potential drug target for mitigating TS risk. Our study not only reveals potential therapeutic targets but also provides directions for future TS drug development.