Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study.
BACKGROUND
Recent investigation suggests that a reversible glutamatergically mediated thalamocortical-striatal dysfunction may serve as a reliable pathophysiological and treatment response marker for obsessive-compulsive disorder (OCD). We postulated that N-methyl- d-aspartate (NMDA) receptors were involved in OCD, and specifically that polymorphisms in the 3' untranslated region of GRIN2B (glutamate receptor, ionotropic, N-methyl- d-aspartate 2B) were associated with OCD in affected families.


OBJECTIVE
The objective of this investigation was to test the association between GRIN2B variants and transmission of the OCD trait using a family-based design.


METHODS
Using the Family Based Association Test (FBAT), we tested for association with OCD diagnosis in 130 families, and also performed a haplotype analysis. FBAT was additionally used in a subset of 98 families to test for association with the quantitative phenotype of lifetime OCD symptom severity. RESULTS. Under a non-additive model of inheritance, the 5072T/G variant was significantly associated with OCD even after correcting for the number of models tested ( P=0.014). In addition, there was a significant positive association with OCD diagnosis ( P=0.002) for the 5072G-5988T haplotype under the recessive model.


CONCLUSIONS
Although preliminary and requiring replication in larger samples, these results provide evidence that GRIN2B may be associated with susceptibility to OCD. Coupled with basic neuroscience and clinical neuroimaging findings in patients with OCD, our results provide new and converging support for the role of altered glutamatergic neurotransmission in the pathogenesis of OCD.
Arnold
Paul D
PD
Child Psychiatry Program, Neurogenetics Section, 1st Floor, Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8. paul_arnold@camh.net
Rosenberg
David R
DR
Mundo
Emanuela
E
Tharmalingam
Subi
S
Kennedy
James L
JL
Richter
Margaret A
MA
D020413:3' Untranslated Regions / Q000235:genetics; D000483:Alleles; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009771:Obsessive-Compulsive Disorder / Q000145:classification / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D012333:RNA, Messenger / Q000096:biosynthesis; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D020413:3' Untranslated Regions; C121001:NR2B NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate