Although the current sample of 1496 TS cases and 5249 controls is the largest studied to date, no loci in our analysis reached the widely accepted statistical threshold for genome-wide significance of p≤5 × 10−8.31-32 This observation is not surprising, given that GWA studies for other highly heritable neuropsychiatric diseases (e.g., autism, bipolar disorder and schizophrenia) have required sample sizes of 5000-10000 cases to identify definitive common risk alleles with modest effect sizes (odds ratios <1.3).33 However, the marginal enrichment of functional brain variants (eQTLs and mQTLs) within the top loci in the primary meta-analysis (Figure 2) suggests that a subset of top signals in our analysis are true associations that may contribute to TS risk through effects on gene expression and methylation. In particular, the trend toward enrichment of frontal cortex eQTLs compared to eQTLs in cerebellum and LCLs is anatomically consistent with the hypothesis that TS is caused by abnormalities in fronto-striatal circuitry.34 Nonetheless, given the nominal significance of these enrichment results, further studies in larger samples are needed before drawing definitive conclusions.
