Common and rare alleles of the serotonin transporter gene,SLC6A4, associated with Tourette's disorder |
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| Authors: | Pablo R Moya PhD Jens R Wendland MD Liza M Rubenstein Kiara R Timpano PhD Gary A Heiman MD Jay A Tischfield MD Robert A King MD Anne M Andrews PhD Samanda Ramamoorthy PhD Francis J McMahon MD Dennis L Murphy MD |
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| Institution: | 1. Laboratory of Clinical Science, National Institute of Mental Health‐Intramural Research Program, , Bethesda, Maryland, USA;2. Department of Physiology, Faculty of Sciences, University of Valparaiso, , Valparaiso, Chile;3. Department of Psychology, University of Miami, , Coral Gables, Florida, USA;4. Human Genetics Institute of New Jersey and Department of Genetics, Rutgers University, , Piscataway, New Jersey, USA;5. Child Study Center of Yale University, , New Haven, Connecticut, USA;6. Semel Institute for Neuroscience and Human Behavior and California Nano Systems Institute, University of California‐Los Angeles, , Los Angeles, California, USA;7. Department of Pharmacology and Toxicology, Virginia Commonwealth University, , Richmond, Virginia, USA;8. Human Genetics Branch, National Institute of Mental Health‐Intramural Research Program, , Bethesda, Maryland, USA |
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| Abstract: | To evaluate the hypothesis that functionally over‐expressing alleles of the serotonin transporter (SERT) gene (solute carrier family 6, member 4, SLC6A4) 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 SLC6A4 promoter plus the rare coding variant SERT isoleucine‐to‐valine at position 425 (I425V). The higher expressing 5‐HTTLPR/rs25531 LA allele was more prevalent in TD probands than in controls (χ2 = 5.75; P = 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; P = 0.0006; OR, 2.29). Likewise, the higher expressing LAC haplotype (5‐HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls (P = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group (P = 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 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 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 Movement Disorder Society |
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| Keywords: | SLC6A4 serotonin transporter (SERT) Tourette's serotonin 5‐HTTLPR SERT isoleucine‐to‐valine substitution (I425V) |
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