Our genome-wide cell and tissue-based enrichment analyses implicate modulation of gene expression through non-coding variants as a fundamental mechanism in Tourette syndrome pathogenesis. All of the top tissues in the enrichment analyses were derived from brain, although dorsolateral pre-frontal cortex (BA9) was the only tissue in which eQTL enrichment surpassed Bonferroni correction. The 5 tissues with the strongest eQTL enrichment (frontal cortex, caudate, putamen, nucleus accumbens and cerebellum) all represent key nodes within the cortico-striatal and cortico-cerebellar circuits that have been implicated in Tourette pathophysiology (1). These results support the hypothesis that Tourette syndrome is a developmental circuit disorder affecting motor, cognitive and behavioral control (as manifested by tics, ADHD, and OCD symptoms), and suggest that future GWAS analyses in larger datasets should aid in identifying not only the individual genes underlying Tourette syndrome susceptibility, but also core pathways in development and/or regulation of these circuits that could serve as targets for modulation-based therapies.
