Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder. Issue 9 (29th April 2013)

• Record Type: Journal Article
• Authors: Moya, Pablo R.; Wendland, Jens R.; Rubenstein, Liza M.; Timpano, Kiara R.; Heiman, Gary A.; Tischfield, Jay A.; King, Robert A.; Andrews, Anne M.; Ramamoorthy, Samanda; McMahon, Francis J.; Murphy, Dennis L.
• Is Part Of: Movement disorders. Volume 28:Issue 9(2013)
• Page Start: 1263
• Page End: 1270
• Publication Date: 2013-04-29
• Subjects: Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.25460
• Languages: English
• ISSNs: 0885-3185

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>To evaluate the hypothesis that functionally over‐expressing alleles of the serotonin transporter (SERT) gene (solute carrier family 6, member 4, <italic>SLC6A4</italic>) are present in Tourette's disorder (TD), just as we previously observed in obsessive compulsive disorder (OCD), we evaluated TD probands (N = 151) and controls (N = 858). We genotyped the refined SERT‐linked polymorphic region 5‐HTTLPR/rs25531 and the associated rs25532 variant in the <italic>SLC6A4</italic> promoter plus the rare coding variant SERT isoleucine‐to‐valine at position 425 (I425V). The higher expressing 5‐HTTLPR/rs25531 L<sub>A</sub> allele was more prevalent in TD probands than in controls (χ<sup>2</sup> = 5.75; <italic>P</italic> = 0.017; odds ratio [OR], 1.35); and, in a secondary analysis, surprisingly, it was significantly more frequent in probands who had TD alone than in those who had TD plus OCD (Fisher's exact test; <italic>P</italic> = 0.0006; OR, 2.29). Likewise, the higher expressing L<sub>AC</sub> haplotype (5‐HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls (<italic>P</italic> = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group (<italic>P</italic> = 0.0013; OR, 2.14). Furthermore, the rare gain‐of‐function SERT I425V variant was observed in 3 male siblings with TD and/or OCD and in their father. Thus, the cumulative count of SERT I425V becomes 1.57% in OCD/TD spectrum conditions versus 0.15% in controls, with a recalculated, family‐adjusted significance of χ<sup>2</sup> = 15.03 (<italic>P</italic> < 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 of which are associated with SERT gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. The present results call for replication in a similarly intensively evaluated sample. © 2013 <italic>Movement</italic> Disorder Society</p> </abstract>