A Haplotype Containing Quantitative Trait Loci for SLC1A1 Gene Expression and Its Association With Obsessive-Compulsive Disorder

Abstract

Context Recent evidence from linkage analyses and follow-up candidate gene studies supports the involvement of SLC1A1, which encodes the neuronal glutamate transporter, in the development of obsessive-compulsive disorder (OCD). Objectives To determine the role of genetic variation of SLC1A1 in OCD in a large case-control study and to better understand how SLC1A1 variation affects functionality. Design A case-control study. Setting Publicly accessible SLC1A1 expression and genotype data. Patients Three hundred twenty-five OCD probands and 662 ethnically and sex-matched controls. Interventions Probands were assessed with the Structured Clinical Interview for DSM-IV, the Yale-Brown Obsessive Compulsive Scale, and the Saving Inventory–Revised. Six single-nucleotide polymorphisms (SNPs) were genotyped. Multiple testing corrections for single-marker and haplotype analyses were performed by permutation. Results Gene expression of SLC1A1 is heritable in lymphoblastoid cell lines. We identified 3 SNPs in or near SLC1A1 that correlated with gene expression levels, 1 of which had previously been associated with OCD. Two of these SNPs also predicted expression levels in human brain tissue, and 1 SNP was further functional in reporter gene studies. Two haplotypes at 3 SNPs, rs3087879, rs301430, and rs7858819, were significantly associated with OCD after multiple-testing correction and contained 2 SNPs associated with expression levels. In addition, another SNP correlating with SLC1A1 gene expression, rs3933331, was associated with an OCD-hoarding subphenotype as assessed by 2 independent, validated scales. Conclusions Our case-control data corroborate previous smaller family-based studies that indicated that SLC1A1 is a susceptibility locus for OCD. The expression and genotype database–mining approach we used provides a potentially useful complementary approach to strengthen future candidate gene studies in neuropsychiatric and other disorders.

Neuromodulation for Obsessive–Compulsive Disorder

“…These measurements include both intracellular and synaptic glutamate, and are consistent with increased caudate activity previously reported in OCD. Gene linkage analyses of patients with OCD and their families also support a pathophysiological role for glutamate [24][25][26][27]. Also, preliminary evidence suggests that glutamatergic agents such as riluzole and ketamine may be useful in OCD [28][29][30][31].…”

Hoarding disorder: a new diagnosis for DSM-V?

“…[68] Genetic studies to date have been conducted in the context of other disorders, such as Tourette's Syndrome [69] or OCD. [34,[70][71][72] Their results have been inconsistent, but are broadly supportive of the idea that hoarding is etiologically distinct from OCD. Finally, the fact that hoarding symptoms tend to be less responsive to evidence-based treatments for OCD, including exposure and ritual prevention and serotonin reuptake inhibitors, [7,36,73,74] further supports the idea of different etiological mechanisms in compulsive hoarding and OCD.…”

Association between the NMDA glutamate receptor GRIN2B gene and obsessive–compulsive disorder

“…The gene that encodes the neuronal glutamate transporter (SLC1A1) has been the most extensively studied. A sex-specific association between SLC1A1 and OCD in male, but not in female, patients has been reported, [12][13][14][15][16] although negative results have also been published. 17 Preliminary results also suggest a possible association between OCD and genetic variations of certain ionotropic glutamate receptors, including GRIK2 (glutamate receptor, ionotropic, kainate 2) 18,19 and GRIN2B (ionotropic glutamate receptor, N-methyl-D-aspartate subunit 2B).…”