To evaluate the hypothesis that functionally over-expressing alleles of the serotonin transporter gene SLC6A4 are present in Tourette disorder (TD), just as we have found in obsessive compulsive disorder (OCD), we evaluated TD probands (N=151) and controls (N=858).

We genotyped the refined 5-HTTLPR/rs25531 locus and the associated rs25532 variant in the SLC6A4 promoter plus the rare coding variant SERT I425V.

The higher-expressing 5-HTTLPR/rs25531 L_A allele was more prevalent in TD probands than controls (χ²=5.75, p=0.017, OR=1.35), and in a secondary analysis, surprisingly found to be significantly more frequent in probands with TD alone than in those with TD plus OCD (Fisher's exact test, p=0.0006, OR=2.29). Likewise, the higher-expressing L_AC haplotype (5-HTTLPR/rs25531/rs25532) was more frequent in TD probands than controls (p=0.024, OR=1.33) and likewise in the TD alone versus TD plus OCD group (p=0.0013, OR=2.14). Further, the rare gain-of-function SERT I425V variant was found in three male siblings with TD and/or OCD and in their father. The cumulative count of SERT I425V thus becomes 1.57% in OCD/TD spectrum conditions vs. 0.15% in controls, with a recalculated, family-adjusted significance of χ²=15.03, p < 0.0001, OR=9.0 (total worldwide genotyped=2914).

This report provides a unique combination of common and rare variants in one gene in TD, all found to be associated with SLC6A4 gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. Present results call for replication in a similarly intensively evaluated sample.