A Primary Candidate Gene for Obsessive-compulsive Disorder

Leckman, James F.; Kim, Young-Shin

doi:10.1001/archpsyc.63.7.717

Cited by 16 publications

(10 citation statements)

References 46 publications

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“…Interestingly, SLC1A1 was the first positional candidate gene in the anxiety disorder obsessive compulsive disorder (OCD) [ 76 , 77 ]. Among OCD positional candidate genes, SLC1A1 has among the strongest support for its association with this disorder [ 78 – 84 ]. Additionally, variations in SLC1A1 gene have also been associated with other forms of anxiety disorders, including posttraumatic stress disorder (PTSD) or anxiety symptom severity in autism spectrum disorder (ASD) [ 85 , 86 ].…”

Section: Discussionmentioning

confidence: 99%

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

2017

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We previously reported a 84-Kb hemi-deletion copy number variant at the SLC1A1 gene locus that reduces its expression and appeared causally linked to schizophrenia. In this report, we characterize the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which more closely model the hemi-deletion we found in human subjects, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Behavioral changes in the HET mice were accompanied by reduced thickness of the dorsomedial prefrontal cortex. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood. Moreover, the brains of Slc1a1+/- mice displayed elevated levels of oxidized glutathione, a trend for increased oxidative DNA damage, and significantly increased levels of cytokines. This latter finding was further supported by SLC1A1 knockdown and overexpression studies in differentiated human neuroblastoma cells, which led to decreased or increased cytokine expression, respectively. Taken together, our results suggest that partial loss of the Slc1a1 gene in mice causes haploinsufficiency associated with behavioral, histological and biochemical changes that reflect an altered redox state and may promote the expression of behavioral features and inflammatory states consistent with those observed in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

2017

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“…However, recently two independent groups of investigators have reported statistically significant association between OCD and a locus on chromosome 9p24 that codes for a high-affinity neuronal/epithelial excitatory amino acid transporter (EAAC-1), also known as SLC1A1 (Solute carrier family 1, member 1) [50,51]. It is thought that in the brain this transporter is crucial in terminating the action of the excitatory neurotransmitter glutamate and in maintaining extracellular glutamate concentrations within a normal range [52]. Although not conclusive, evidence from genetic studies add to the growing body of evidence implicating glutamatergic abnormalities in OCD.…”

Section: Evidence From Genetic Studiesmentioning

confidence: 99%

Glutamatergic Dysfunction-Newer Targets for Anti-Obsessional Drugs

Bhattacharyya¹,

Chakraborty²

2007

RPCN

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Despite widespread use and validation of their efficacy, about 40-60% of obsessive compulsive disorder (OCD) sufferers do not respond to appropriate courses of treatment with serotonin reuptake inhibitors (SRI) and even with the combination of pharmacotherapy and cognitive behaviour therapy a substantial number of patients remain dramatically symptomatic. Recently, there has been increasing interest in investigating glutamatergic dysfunction in OCD. Multiple lines of evidence point toward glutamatergic dysfunction being related to the pathophysiology of OCD, with glutamate modulating drugs being an alternative pharmacological strategy for treating OCD. In this article we focus in detail on the rationale for targeting glutamatergic agents as well as review the recent important patents for compounds that have emerged from these studies.

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“…SLC1A1 is a neuronal gluamate transporter genes and is a promising candidate gene for obsessive‐compulsive disorder (OCD) [Leckman and Kim, 2006]. This gene is expressed in the cortex, striatum, and thalamus, where it is important for glutamate neurotransmission [Kanai and Hediger, 2004].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive family‐based association study of the glutamate transporter gene SLC1A1 in obsessive‐compulsive disorder

Samuels

Wang

Riddle

et al. 2011

American J of Med Genetics Pt B

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SLC1A1 encodes a neuronal glutamate transporter and is a promising candidate gene for obsessive-compulsive disorder (OCD). Several independent research groups have reported significant associations between OCD and single nucleotide polymorphisms (SNPs) in this gene. Previously, we evaluated 13 SNPs in, or near, SLC1A1 and reported a strong association signal with rs301443, a SNP 7.5 kb downstream of the gene (Shugart et al., 2009). The aims of the current study were first, to further investigate this finding by saturating the region around rs301443; and second, to explore the entire gene more thoroughly with a dense panel of SNP markers. We genotyped an additional 111 SNPs in or near SLC1A1, covering from 9kb upstream to 84kb downstream of the gene at average spacing of 1.7kb per SNP, and conducted family-based association analyses in 1,576 participants in 377 families. We found that none of the surrounding markers were in linkage disequilibrium with rs301443, nor were any associated with OCD. We also found that SNP rs4740788, located about 8.8 kb upstream of the gene, was associated with OCD in all families (P=0.003) and in families with male affecteds (P=0.002). A 3-SNP haplotype (rs4740788-rs10491734-rs10491733) was associated with OCD in the total sample (P=0.00015) and in families with male affecteds (P=0.0007). Although of nominal statistical significance considering the number of comparisons, these findings provide further support for the involvement of SLC1A1 in the pathogenesis of OCD.

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A Primary Candidate Gene for Obsessive-compulsive Disorder

Cited by 16 publications

References 46 publications

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

Glutamatergic Dysfunction-Newer Targets for Anti-Obsessional Drugs

Comprehensive family‐based association study of the glutamate transporter gene SLC1A1 in obsessive‐compulsive disorder

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