SLC1A1, which encodes the neuronal and epithelial glutamate transporter, is a promising candidate gene for obsessive-compulsive disorder (OCD). In this study, we conducted capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) screen for all 12 identified exons, including all coding regions and approximately 50 bp of flanking introns of the human SLC1A1 in 378 OCD-affected individuals. Full sequencing was completed on samples that showed an aberrant SSCP tracing for identification of the underlying sequence variants. Our aim was to determine if there are differences in the frequencies of relatively common alleles, or rare functional alleles, in 378 OCD cases and 281 ethnically matched controls. We identified one nonsynonymous coding SNP (c.490A > G, T164A) and three synonymous coding SNP (c.81G > C, A27A; c.414A > G, T138T; c.1110T > C, T370T) in case samples. We found no statistical differences in genotype and allele frequencies of common cSNPs in SLC1A1 between the OCD cases and controls. The rare variant T164A was found only in one family. Further investigation of this variant is necessary to determine whether and how it is related to OCD. There was no other evidence of significant accumulation of deleterious coding mutations in SLC1A1 in the OCD cases.
"The results from this study demonstrate the need for larger collaborative samples and subphenotyping, and highlight the potential for false-positive findings, or at least the need for cautious interpretation of positive findings, with candidate gene studies. If heterogeneity of the SLC1A1 gene comprises both common and rare variants, then next-generation sequencing may also be productive in future studies of SLC1A1 and OCD [Wang et al., 2010; Bailey et al., 2011]. "
"Our group and others are beginning to search for rare variants of large effect which are more likely to be of causal significance, even if present only in subset of OCD patients. Rare variants identified to date include a rare 11 bp deletion located just 3′ of SLC1A1 (Dickel et al., 2006) and a single rare SNP identified through mutation screening of over 300 OCD patients (Wang et al., 2010). In addition, a recent study of dicarboxylic aminoaciduria, a rare autosomal recessive renal disorder, identified rare mutations in SLC1A1, which were shown to impede glutamate transport in the kidney mediated by the EAAC1 protein expressed in the kidney. "
[Show abstract][Hide abstract] ABSTRACT: Obsessive-compulsive disorder (OCD) is a common and often debilitating neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviors (compulsions) and excessive anxiety. While the neurobiology and etiology of OCD has not been fully elucidated, there is growing evidence that disrupted neurotransmission of glutamate within corticalstriatal-thalamocortical (CSTC) circuitry plays a role in OCD pathogenesis. This review summarizes the findings from neuroimaging, animal model, candidate gene and treatment studies in the context of glutamate signaling dysfunction in OCD. First, studies using magnetic resonance spectroscopy are reviewed demonstrating altered glutamate concentrations in the caudate and anterior cingulate cortex of patients with OCD. Second, knockout mouse models, particularly the DLGAP3 and Sltrk5 knockout mouse models, display remarkably similar phenotypes of compulsive grooming behavior associated with glutamate signaling dysfunction. Third, candidate gene studies have identified associations between variants in glutamate system genes and OCD, particularly for SLC1A1 which has been shown to be associated with OCD in five independent studies. This converging evidence for a role of glutamate in OCD has led to the development of novel treatment strategies involving glutamatergic compounds, particularly riluzole and memantine. We conclude the review by outlining a glutamate hypothesis for OCD, which we hope will inform further research into etiology and treatment for this severe neuropsychiatric condition.
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