Interrogating the genetic determinants of Tourette syndrome and other tic disorders through genome-wide association studies

Objective: Tourette Syndrome is polygenic and highly heritable. Genome-wide association (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette syndrome and other tic disorders. Method: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette syndrome cases and 9,488 controls. Replication of top loci was conducted in an independent, population-based sample (706 cases; 6,068 controls). Relationships between Tourette polygenic risk scores (PRS), other tic disorders, ascertainment, and tic severity were examined. Results: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235 (SNP p=2.1×10−8; Gene p=8.9×10−7), though this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily-conserved regions explained 92.4% of Tourette syndrome heritability (Bonferroni corrected p-value=0.005). Tourette-associated genes were preferentially expressed in human dorsolateral prefrontal cortex (p=1.2×10−4). Tourette PRS predicted both Tourette syndrome (p=5.3×10−9) and tic spectrum disorders (p=4.2 ×10−4) status in the population-based sample. Tourette PRS also correlated with worst-ever tic severity (p=0.026) and was higher in cases with a family history of tics than in simplex cases. Conclusions: Modulation of gene expression through non-coding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette syndrome and other tic disorders in future diagnostic schema. Tourette PRS derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.