Glutamate System Genes Associated with Ventral Prefrontal and Thalamic Volume in Pediatric Obsessive-Compulsive Disorder

Abstract

This pilot study was undertaken to determine if there was a significant association between specific glutamate system genes and regional volumes of interest implicated in the pathogenesis of obsessive-compulsive disorder (OCD). Volumetric magnetic resonance imaging (MRI) and genotyping of 7 polymorphisms in two genes, glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B) and solute linked carrier, family 1, member 1 (SLC1A1) were conducted in 31 psychotropic-naïve pediatric OCD patients. The rs1805476 variant of GRIN2B was associated with left but not right orbital frontal cortex (OFC) (p=0.04) and right but not left anterior cingulate cortex (ACC) volume (p=0.02). The SLC1A1 rs3056 variant was associated with increased total (p=0.01), left (p=0.02) and right (p=0.02) thalamic volume. These results suggest that GRIN2B and SLC1A1 may be associated with regional volumetric alterations in OFC, ACC, and thalamus in children with OCD.

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

“…The imaging genetics findings in OCD related to the 5-HTTLPR are still rather preliminary, and many factors, such as comorbidity, ethnicity, therapy, sex, age (neurodevelopmental factors), and age of onset, should be considered in future studies. Although the genetic studies show one of the highest effect sizes for association of the glutamatergic system and OCD, only few groups have reported findings related to imaging genetics in OCD and genetic variants of glutamatergic genes (Arnold et al, 2009a(Arnold et al, , 2009bWu et al, 2012). The results of these investigations coincide with findings from meta-analyses and GWAS; taken together, these observations support the involvement of the glutamatergic system in OCD (Stewart et al, 2013a(Stewart et al, , 2013bTaylor, 2013).…”

“…Therefore, the glutamtergic system is of special interest for imaging genetics. Arnold et al (2009a) reported an increased thalamic volume in OCD patients with the AA genotype of the SLC1A1 (solute carrier family 1 (neuronal/ epithelial high affinity glutamate transporter), member 1) rs3056 variant. SLC1A1 gene encodes a high-affinity excitatory amino acid transporter which is selectively expressed in the central nervous system.…”

“…In contrast, Wu et al (2012) uncovered a trend between rs301430 in SLC1A1 and increased thalamic volume. Both observations might be caused by transcriptional alterations, because both variants lie in the 3 0 untranslated region of the SLC1A1 gene (Arnold et al, 2009a;Wendland et al, 2009). 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.…”

“…Moreover, the NMDA receptors are thought to be involved in neurodevelopmental processes of the nervous system, as with the GRIN2B and GRIN2A (Endele et al, 2010;Hall et al, 2007). Although a meta-analysis by Taylor (2013) found no association between GRIN2B and OCD, imaging-genetic findings suggest that GRIN2B affects glutamatergic concentrations in the ACC of OCD patients (Arnold et al, 2009b), as well as volumes in the ACC, OFC (Arnold et al, 2009a), and thalamus (Wu et al, 2012). Moreover, a new candidate gene for OCD risk, which encodes DLGAP (SAPAP-related) (Bienvenu et al, 2009;Stewart et al, 2013b;Zü chner et al, 2009), was recently reported to affect ACC and OFC volume in OCD (Wu et al, 2012).…”

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

“…43 Recent neuro imaging studies suggest that this symptom dimension may be mediated by a specific neural substrate, mainly comprising the insula; 44 prefrontal cortical areas, 45 such as the ventromedial prefrontal regions including the anterior cingulate, orbitofrontal gyri and ventrolateral prefrontal cortex; 46 and the caudate nucleus. 46,47 Arnold and colleagues 48 recently reported the association between the C-C haplotype of rs1805476 and decreased left orbitofrontal cortex volume and right anterior cingulate volume compared with carriers of the A allele in a sample of pediatric patients with OCD. The same authors also described a significant association between anterior cingulate glutamatergic concentration and the GRIN2B rs1019385 polymorphism.…”