Glutamate Transporter Gene SLC1A1 Associated With Obsessive-compulsive Disorder

Arnold, Paul; Sicard, Tricia; Burroughs, Eliza; Richter, Margaret A.; Kennedy, James L.

doi:10.1001/archpsyc.63.7.769

Cited by 322 publications

(237 citation statements)

References 51 publications

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“…At least two other genes affecting glutamatergic neurotransmission appear associated with OCD, SLC1A1 [Arnold et al, 2006;Dickel et al, 2006;Stewart et al, 2007] and, more preliminarily, GRIN2B [Arnold et al, 2004]. Again, we found no evidence for an association of Sapap3 with OCD itself, though we cannot rule out the possibility that Sapap3 is relevant to a pathological grooming-related ''subtype'' of OCD (recall that more than 1/3 of the participants with OCD had a GD).…”

Section: Discussioncontrasting

confidence: 69%

Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study

Bienvenu

Wang

Shugart

et al. 2009

American J of Med Genetics Pt B

179

127

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SAP90/PSD95-associated protein (SAPAP) family proteins are post-synaptic density (PSD) components that interact with other proteins to form a key scaffolding complex at excitatory (glutamatergic) synapses. A recent study found that mice with a deletion of the Sapap3 gene groomed themselves excessively, exhibited increased anxiety-like behaviors, and had corticostriatal synaptic defects, all of which were preventable with lentiviral-mediated expression of Sapap3 in the striatum; the behavioral abnormalities were also reversible with fluoxetine. In the current study, we sought to determine whether variation within the human Sapap3 gene was associated with grooming disorders (GDs: pathologic nail biting, pathologic skin picking, and/or trichotillomania) and/or obsessive-compulsive disorder (OCD) in 383 families thoroughly phenotyped for OCD genetic studies. We conducted family-based association analyses using the FBAT and GenAssoc statistical packages. Thirty-two percent of the 1,618 participants met criteria for a GD, and 65% met criteria for OCD. Four of six SNPs were nominally associated (P < 0.05) with at least one GD (genotypic relative risks: 1.6-3.3), and all three haplotypes were nominally associated with at least one GD (permuted P < 0.05). None of the SNPs or haplotypes were significantly associated with OCD itself. We conclude that Sapap3 is a promising functional candidate gene for human GDs, though further work is necessary to confirm this preliminary evidence of association.

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Section: Discussioncontrasting

confidence: 69%

Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study

Bienvenu

Wang

Shugart

et al. 2009

American J of Med Genetics Pt B

179

127

View full text Add to dashboard Cite

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“…It should also be noted that the recent association between 5-HTTLPR and OCD by Hu et al was observed in a case-control as well as in a family-based association study, the latter of which is not susceptible to hidden population stratification. Thus, the lack of association in our study warrants further analyses in large family-based OCD samples such as the OCD Collaborative Genetics Study ) before it will point toward the need to analyze other candidate regions such as 9p, 3q, 7p, 1q, 15q, 6q, and 13q (Hanna et al, 2002;Shugart et al, 2006;Willour et al, 2004) and polymorphisms involved in other neurotransmitters such as glutamate (Arnold et al, 2006;Dickel et al, 2006;Rosenberg and Keshavan, 1998), neuromodulators, and developmental signals potentially of importance in OCD such as glutamate.…”

Section: Discussionmentioning

confidence: 84%

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Wendland

Kruse

Cromer

et al. 2007

Neuropsychopharmacol

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Both serotonin transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) genes have shown positive associations with obsessive-compulsive disorder (OCD) and some other psychiatric disorders, but these results have not been consistently replicated. To explore the hypothesis that this variability might result from the effects of differing combinations of overlooked variants within SLC6A4 together with small OCD and control sample sizes, we studied three common functional polymorphisms (5-HTTLPR, STin2, and the newly discovered SNP, rs25531) in the largest sample size of OCD patients (N ¼ 347) and controls (N ¼ 749) ever investigated. During methods development, we found evidence for potential SLC6A4 genotyping problems with earlier methodology, a third possible contributor to variability in earlier studies. A fourth possible explanation might be SLC6A4 Â BDNF interactions, which prompted us to investigate combined genotypes of BDNF V66M with the three SLC6A4 loci. Except for a nominal association with rs25531 alone, which did not survive correction for multiple comparisons, we found no evidence for any of these other variants being associated alone or together with OCD, and we therefore also examined clinical OCD subtypes within the sample to evaluate clinical heterogeneity. Subgroups based on the age of OCD onset, gender, familiality, factor analysis-derived symptom dimensions, or comorbidity with other psychiatric disorders failed to identify SLC6A4-or BDNF-associated phenotypes, with one exception of overall number of comorbid anxiety disorders being significantly associated with 5-HTTLPR/rs25531. We conclude that despite their attractiveness as candidate genes in OCD, our data provide no support for association in this large OCD patient sample and point toward the need to examine other genes as candidates for risk determinants in OCD.

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“…Single tests of association under additive and recessive models were assessed using the Family-Based Association Tests (FBAT) program (v. 1.7.1) [Rabinowitz & Laird, 2000]. Recessive models were included because they were used in at least one of the OCD association studies [Arnold et al, 2006]; the additive model of FBAT is presented for comparison. It should be noted that because each SNP is biallelic, the significance of the results for the recessive model is the same as the dominant model (the Z-scores for the alleles are flipped and in the opposite direction).…”

Section: Statistical Analysesmentioning

confidence: 99%

“…This finding was replicated in 42 pedigrees with early onset OCD [Willour et al, 2004]. Subsequently, three studies have reported an association between markers at SLC1A1 and OCD [Arnold, Sicard, Burroughs, Richter, & Kennedy, 2006;Dickel et al, 2006;Stewart et al, 2007a]. The Autism Genome Project, a largescale, collaborative autism genetics research project, identified SLC1A1 in a genome-wide linkage scan of autism due to its proximity to a linkage peak at 9p24.1, and its role in glutamate function [Szatmari et al, 2007].…”

Section: Introductionmentioning

confidence: 98%

“…The aim of the study was to examine if previously associated SNPs in SLC1A1 were associated with autism. Of note, these three SNPs were associated with OCD in one or more of the previous association studies [Arnold et al, 2006;Dickel et al, 2006;Stewart et al, 2007a]. We tested each marker and a previously identified haplotype (rs301430-rs301979) for association in a strictly defined autism sample.…”

Section: Introductionmentioning

confidence: 99%

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Family‐based association testing of OCD‐associated SNPs of SLC1A1 in an autism sample

et al. 2008

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Reports identified the neuronal glutamate transporter gene, SLC1A1 (OMIM 133550, chromosome 9p24), as a positional and functional candidate gene for obsessive-compulsive disorder (OCD). The presence of obsessions and compulsions similar to OCD in autism, the identification of this region in a genome-wide linkage analysis of individuals with autism spectrum disorders (ASDs), and the hypothesized role of glutamate in ASDs make SLC1A1 a candidate gene for ASD as well. To test for association between SLC1A1 and autism, we typed three single nucleotide polymorphisms (SNPs, rs301430, rs301979, rs301434) previously associated with OCD in 86 strictly defined trios with autism. Family-Based Association Tests (FBAT) with additive and recessive models were used to check for association. Additionally, an rs301430-rs301979 haplotype identified for OCD was investigated. FBAT revealed nominally significant association between autism and one SNP under a recessive model. The G allele of rs301979 was undertransmitted (equivalent to overtransmission of the C allele under a dominant model) to individuals with autism (Z 5 À2.47, P 5 0.01). The G allele was also undertransmitted in the T-G haplotype under the recessive model (Z 5 À2.41, P 5 0.02). Both findings were also observed in the male-only sample. However, they did not withstand correction for multiple comparisons.

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Glutamate Transporter Gene SLC1A1 Associated With Obsessive-compulsive Disorder

Cited by 322 publications

References 51 publications

Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study

Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Family‐based association testing of OCD‐associated SNPs of SLC1A1 in an autism sample

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