Glutamate receptor gene (GRIN2B) associated with reduced anterior cingulate glutamatergic concentration in pediatric obsessive–compulsive disorder
Introduction
Obsessive-compulsive disorder (OCD) is a complex genetic disorder, likely involving multiple genes of small effect and environmental factors (Pauls, 2008). Candidate gene studies have been conducted based on a priori etiological hypotheses, one of which postulates altered glutamate neurotransmission (Macmaster et al., 2008). Strong support for this hypothesis comes from proton magnetic resonance spectroscopy (1H-MRS) studies revealing greater glutamatergic concentrations (Glx) in the caudate (Rosenberg et al., 2000) and lower Glx in anterior cingulate cortex (ACC) (Rosenberg et al., 2004) in pediatric OCD patients. This finding was replicated in adults with OCD (Yücel et al., 2008). Recently, we reported associations between OCD and two glutamate system genes: the glutamate subunit receptor GRIN2B (glutamate receptor, ionotropic, N-methyl-D-aspartate 2B) (Arnold et al., 2004), and the glutamate transporter SLC1A1 (solute linked carrier, family 1, member 1) (Arnold et al., 2006, Dickel et al., 2006). These associations have been replicated in independent samples (Arnold, 2007, Stewart et al., 2007).
Intermediate phenotypes derived from neuroimaging may increase power to identify genetic effects (closer link between genotype and phenotype) and delineate pathways linking risk genes to disorders (Meyer-Lindenberg and Weinberger, 2006). To our knowledge, no previous genetic studies of OCD have utilized neuroimaging phenotypes. Therefore, we set out to conduct a proof-of-principle study of an imaging genetics paradigm in which we test associations between glutamate system genes and glutamatergic concentration (Glx) in the anterior cingulate cortex (ACC) as a proposed intermediate phenotype for OCD. We hypothesized that putative risk alleles identified in previous candidate gene studies of GRIN2B and SLC1A1 would be associated with reduced ACC Glx in pediatric OCD patients.
Section snippets
Subjects
Participants included 16 (11 male, 5 female) medication-naïve pediatric OCD patients, aged 7–18 years (mean = 11.0 years, S.D. = 3.1). Eight patients overlap with the sample from a previous investigation measuring ACC Glx, with detailed assessment procedures and inclusion/exclusion criteria described previously (Rosenberg et al., 2004). Written informed consent was obtained from parents/guardians, and written assent from pediatric participants. Patients were administered the Schedule for Affective
Results
The mean absolute concentration of Glx was 9.94 millimoles (mM) for the ACC and 10.38 mM for the OCC. The mean SD for Glx was 6.53 mM (range 5 to 31 mM) for the ACC and 7.20 mM (range 4–31 mM) for the OCC. The only statistically significant association was between GRIN2B-rs1019385 and ACC Glx. Decreased ACC Glx was seen with the G/G genotype compared with the T/G or T/T genotype compared with T/G or T/T (F = 6.2 (1, 13), P = 0.03). ACC Glx values for rs1019385 genotype groups were normally
Discussion
In this preliminary study, we found a significant association between ACC but not OCC Glx and the GRIN2B-rs1019385 polymorphism, with GG individuals exhibiting decreased Glx compared with carriers of the T allele. Our family-based studies have found the G allele (GG genotype specifically) to be associated with OCD (Arnold, 2007). The G allele of rs1019385 is a promoter region variant that leads to reduced transcription (Miyatake et al., 2002), which could affect glutamate neurotransmission. The
Acknowledgments
We thank Ms. Tamara Arenovich of the Biostatistics Unit of the Centre for Addiction and Mental Health for statistical support and consultation. We also thank Mr. S.M. Shaheen for editorial assistance.
Support was provided by the Ontario Mental Health Foundation through a Type B grant (PDA, MAR, JLK), the Canadian Institutes for Health Research through an operating grant (MOP-38077) (PDA, EM, JLK, MAR) and a Fellowship to Dr. Arnold, the National Alliance on Research in Schizophrenia and
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