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Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study

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Abstract

Rationale

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.

Objectives

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.

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Acknowledgements

Valuable assistance from Sajid Shaikh, Nicole King, Mary Smirniw, Joanna McBride, Vytas Velyvis, and Eliza Burroughs is appreciated. This study was performed in compliance with the laws of Canada and the province of Ontario.

Financial support was provided by the Ontario Mental Health Foundation through a Research Training Fellowship (P.D.A.) and Type B grant (P.D.A., E.M., J.L.K., M.A.R.), and the Canadian Institutes for Health Research (MOP-38077) (P.D.A., E.M., J.L.K., M.A.R.). Dr. Rosenberg receives support from the State of Michigan Joe F. Young Sr Psychiatric Research and Training Program, the Miriam L. Hamburger Endowed Chair at Children’s Hospital of Michigan and Wayne State University, Detroit, Mich., USA and the National Institute of Mental Health (R01MH59299; RO1MH065122; K24MH02037).

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Authors and Affiliations

  1. Child Psychiatry Program, Neurogenetics Section, 1st Floor, Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, ON, Canada, M5T 1R8

    Paul D. Arnold

  2. Department of Psychiatry, Children’s Hospital of Michigan, Wayne State University, Psychiatry 9B 4201 St Antoine Boulevard, Detroit, MI 48201, USA

    David R. Rosenberg

  3. Neurogenetics Section, R-30, Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, ON, Canada, M5T 1R8

    Emanuela Mundo, Subi Tharmalingam & James L. Kennedy

  4. Anxiety Disorders Clinic, 11th floor, Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, ON, Canada, M5T 1R8

    Margaret A. Richter

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  1. Paul D. Arnold
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Correspondence to Paul D. Arnold.

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Arnold, P.D., Rosenberg, D.R., Mundo, E. et al. Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study. Psychopharmacology 174, 530–538 (2004). https://doi.org/10.1007/s00213-004-1847-1

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