Genomic organization of the SLC1A1/EAAC1 gene and mutation screening in early-onset obsessive-compulsive disorder

Abstract

The first genome scan conducted in early-onset obsessive-compulsive disorder used a nonparametric analysis to identify a peak in a region of chromosome 9 containing the gene SLC1A1, which codes for the neuronal and epithelial glutamate transporter EAAC1. Interaction between the glutamatergic and serotonergic systems within the striatum suggests EAAC1 as a functional candidate in OCD as well. We determined the genomic organization of SLC1A1 primarily by using primers designed from cDNA sequence to amplify from adaptor-ligated genomic DNA restriction fragments. In order to confirm SLC1A1 as a positional candidate in early-onset OCD, common single nucleotide polymorphisms (SNPs) were identified that enabled mapping of SLC1A1 within the region of the lod score peak. Based on the linkage evidence, the coding region was sequenced in the probands of the seven families included in the genome scan. No evidence was found for a functional mutation, but several SNPs were identified. Capillary electrophoresis SSCP typing of a haplotype consisting of two common SNPs within EAAC1 revealed no significant linkage disequilibrium. Molecular Psychiatry (2001) 6, 160-167.

Linkage and association studies of anxiety disorders

“…[93] Direct sequencing of this gene has so far not uncovered any potentially functional mutations. [94,95] Overall, there appears to be ongoing association between OCD and SLC1A1, although the inconsistency between studies regarding the associated SNPs strongly suggests that untyped SNPs in varying measures of linkage disequilibrium with the reported SNPs are driving the signal.…”

Obsessive-compulsive disorder phenotypes: implications for genetic studies

“…The same group sequenced the LOD score peak region identified in this genome scan and found no evidence for a functional mutation in the SLC1A1 gene. 41 In sum, the early-onset phenotype is characterized by a male preponderance 24,42 , a higher frequency of compulsions not preceded by obsessions, 19,21 higher comorbidity with tics and TS 20,28 and worse response to monotherapy treatment with clomipramine or SRI. 21,35 Furthermore, the early-onset phenotype has been associated with increased familial loading for OCD.…”

Evidence for a heritable unidimensional symptom factor underlying obsessionality

“…Despite the increased incidence of subclinical obsessive-compulsive symptoms in OCD families, however, the etiological relationship between OCD, subclinical OCD, and non-clinical obsessionality is still not entirely clear. To date, definite susceptibility genes for OCD and obsessionality have not yet been identified, due in part to phenotypic and likely etiologic heterogeneity [Leonard et al, 1990;Apter et al, 1996;Veenstra-VanderWeele et al, 2001;Brynska and Wolanczyk, 2005;Yao et al, 2005;Arnold et al, 2006;Hemmings and Stein, 2006;Shugart et al, 2006].…”