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

Abstract

Background: Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neuro transmission in the pathogenesis of obsessive-compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes. Methods: Between 2003 and 2008, we performed a case-control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′ UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions. Results: We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37-4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22-3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions. Limitations: Study limitations included the risk of population stratification associated with the case-control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3′ UTR and exon 13 of GRIN2B. Conclusion: Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder.

Imaging genetics in obsessive-compulsive disorder: Linking genetic variations to alterations in neuroimaging

“…In addition to the glutamate transporter the N-methyl-D-aspartate (NMDA) receptors, a class of ionotropic glutamate receptors, are of special interest in OCD. Not only that NMDA receptor gene variants were suggested to associate with OCD (Alonso et al, 2012), dysfunction of NMDA receptors neurotransmission activity were suggested to be involved in OCD (Richter et al, 2012) as well as to mediate fear conditions (Davis, 2011). The NMDA receptor channels are heteromers, composed of three different subunits: NR1 (GRIN1), NR2 (GRIN2A, GRIN2B, GRIN2C, or GRIN2D).…”

Rodent models of obsessive compulsive disorder: Evaluating validity to interpret emerging neurobiology

“…Additional candidate genes in the glutamate system have also been studied, including GRIN2B , which shows evidence of association in some but not all studies (Arnold et al, 2004, Alonso et al, 2012, Cai et al, 2013). The other leading candidate gene is the serotonin transporter, SLC6A4 , with both common and rare variants exhibiting association in some studies (Ozaki et al, 2003, Dickel et al, 2007, Grados et al, 2007, Saiz et al, 2008, Wendland et al, 2008), but not all (Taylor, 2013).…”

Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene

“…Genetic variations in NMDA receptors have been implicated in the genetic susceptibility to neurological, psychiatric and learning disorders, e.g. obsessive-compulsive disorder [12], attention deficit/hyperactivity disorder (ADHD) [13], dyslexia [14], schizophrenia and bipolar disorders [15], Parkinson disease and Huntington disease [16]. It is still an open debate whether patients with GRIN2B mutations present with an unspecific ID phenotype with some anomalies in behavior, or with a very specific behavioral phenotype that could lead to the suspicion of a GRIN2B mutation on clinical evidence alone.…”