Glutamate system genes and brain volume alterations in pediatric obsessive-compulsive disorder: A preliminary study

Abstract

Obsessive-compulsive disorder (OCD) has been associated with regional volumetric brain abnormalities, which provide promising intermediate phenotypes of the disorder. In this study, volumes of brain regions selected for a priori evidence of association with OCD (orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), thalamus, caudate, putamen, globus pallidus and pituitary) were measured using structural magnetic resonance imaging (MRI) in 20 psychotropic-naïve pediatric OCD patients. We examined the association between these regional brain volumes and a total of 519 single nucleotide polymorphisms (SNPs) from nine glutamatergic candidate genes (DLGAP1, DLGAP2, DLGAP3, GRIN2B, SLC1A1, GRIK2, GRIK3, SLITRK1 and SLITRK5). These genes were selected based on either previous reported association with OCD in humans or evidence from animal models of OCD. After correcting for multiple comparisons by permutation testing, no SNP remained significantly associated with volumetric changes. The strongest trend toward association was identified between two SNPs in DLGAP2 (rs6558484 and rs7014992) and OFC white matter volume (P = 0.000565, Padjusted= 0.3071). Our other top ranked association findings were with ACC, OFC and thalamus. These preliminary results suggest that sequence variants in glutamate candidate genes may be associated with structural neuroimaging phenotypes of OCD.

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

“…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).…”

“…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).…”

“…Notably, genetic susceptibility effects are mediated by molecular and cellular mechanisms, which in turn modulate behavioral phenotypes by affecting the structural and functional properties of neural circuits (Atmaca et al, 2011;Hesse et al, 2011;MacMaster, 2010;Wu et al, 2012). Therefore, such translational studies that implement genetics and imaging techniques may reveal the etiology of OCD more precisely (MacMaster, 2010).…”

Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review

“…For the DLG4 gene, SNPs (Table 1) and CNVs (Table 3) have been identified only in patients with schizophrenia and with 84 Zanni et al 83 Philips et al 84 Kantojärvi et al 115,116 rs2301963 (associated with decreased orbitofrontal cortex white matter volume) 117 Chien et al 115 Li et al 116 Wu et al 125 Spellmann et al 122 Zhao et al 123 De Luca et al 124 Strauss et al autism-spectrum disorders, respectively. In contrast, SNVs have been associated with both disorders (Table 2).…”

Sintomas obsessivo-compulsivos em escolares: prevalência, dimensões psicopatológicas, agregação familiar, comorbidades e fatores clínicos associados

“…Interestingly, glutamatergic candidate genes (DLGAP2) have shown a strong trend towards significant association with pre-frontal volumetric changes in a pediatric OCD sample (65), but further studies are required to establish the relationship between candidate genes and physiology of OCD. A recent whole genome association study found an association between OCD and DLGAP1, a member of the neuronal postsynaptic density complex.…”