A Candidate Gene Study of Tardive Dyskinesia in the CATIE Schizophrenia Trial
Tardive dyskinesia (TD) is a movement disorder characterized by involuntary oro-facial, limb, and truncal movements. As a genetic basis for inter-individual variation is assumed, there have been a sizeable number of candidate gene studies. All subjects met diagnostic criteria for schizophrenia and were randomized to receive antipsychotic medications as participants in the Clinical Antipsychotic Trials of Intervention Effectiveness project (CATIE). TD was assessed via the Abnormal Involuntary Movement Scale at regular intervals. Probable TD was defined as meeting Schooler-Kane criteria at any scheduled CATIE visit (207/710 subjects, 29.2%). A total of 128 candidate genes were studied in 710 subjects-2,580 SNPs in 118 candidate genes selected from the literature (e.g., dopamine, serotonin, glutamate, and GABA pathways) and composite genotypes for 10 drug-metabolizing enzymes. No single marker or haplotype association reached statistical significance after adjustment for multiple comparisons. Thus, we found no support for either novel or prior associations from the literature.
Available from: Jeffrey A Lieberman
- "Recently, SLC18A2 variants have also been associated with nonaffective psychotic disorder and performance in a comprehensive neurocognitive test battery (Simons and van Winkel, 2013). Furthermore, the rs2015586 marker in the SLC18A2 gene was the top finding in a large association study of 128 candidate genes with TD occurrence in the CATIE sample (Tsai et al., 2010), making it an important gene for further investigation in TD occurrence and severity. "
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ABSTRACT: Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular monoamine transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample (Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD.
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