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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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References

  • Alsobrook J, Leckman J, Goodman W, Rasmussen S, Pauls D (1999) Segregation analysis of obsessive-compulsive disorder using symptom-based factor scores. Am J Med Genet (Neuropsychiatr Genet) 88:669–675

    Google Scholar 

  • Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F (2000) Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 47:305–313

    Google Scholar 

  • Basile VS, Masellis M, Potkin SG, Kennedy JL (2002) Pharmacogenomics in schizophrenia: the quest for individualized therapy. Hum Mol Genet 11:2517–2530

    Article  CAS  PubMed  Google Scholar 

  • Baxter LR Jr, Schwartz JM, Bergman KS, Szuba MP, Guze BH, Mazziotta JC, Alazraki A, Selin CE, Ferng HK, Munford P et al. (1992) Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder. Arch Gen Psychiatry 49:681–689

    CAS  PubMed  Google Scholar 

  • Bolton J, Moore G, MacMillan S, Stewart C, Rosenberg D (2001) Case study: caudate glutamatergic changes with paroxetine persist after medication discontinuation in pediatric OCD. J Am Acad Child Adolesc Psychiatry 40:903–906

    Article  CAS  PubMed  Google Scholar 

  • Brody AL, Saxena S, Schwartz JM, Stoessel PW, Maidment K, Phelps ME, Baxter LR Jr (1998) FDG-PET predictors of response to behavioral therapy and pharmacotherapy in obsessive compulsive disorder. Psychiatry Res 84:1–6

    Article  CAS  PubMed  Google Scholar 

  • Bronstein Y, Cummings J (2001) Neurochemistry of frontal-subcortical circuits. In: Lichter D, Cummings J (eds) Frontal-subcortical circuits in psychiatric and neurological disorders. Guilford, New York, pp 59–91

  • Camarena B, Nicolini H (2002) Family-based association analysis of 5-HT1Db receptor gene in obsessive-compulsive disorder. Int J Neuropsychopharmacol 5:S116

    Google Scholar 

  • Carey G, Gottesman I (1981) Twin and family studies of anxiety, phobic and obsessive disorders. In: Klein D, Rabkin J (eds) Anxiety: new research and changing concepts. Raven, New York

  • Cavallini MC, Pasquale L, Bellodi L, Smeraldi E (1999) Complex segregation analysis for obsessive compulsive disorder and related disorders. Am J Med Genet 88:38–43

    Article  CAS  PubMed  Google Scholar 

  • Chakravarti A (1999) Population genetics—making sense out of sequence. Nat Genet 21:56–60

    CAS  PubMed  Google Scholar 

  • Cheramy A, Romo R, Glowinski J (1986) The relative roles of neuronal activity and direct presynaptic mechanisms in controlling the release of dopamine from the cat caudate nucleus. Ann N Y Acad Sci 473:80–91

    CAS  PubMed  Google Scholar 

  • Cheramy A, Barbeito L, Godeheu G, Glowinski J (1992) Riluzole inhibits the release of glutamate in the caudate nucleus of the cat in vivo. Neurosci Lett 147:209–212

    Article  CAS  PubMed  Google Scholar 

  • Conne B, Stutz A, Vassalli JD (2000) The 3′ untranslated region of messenger RNA: a molecular “hotspot” for pathology? Nat Med 6:637–641

    Article  CAS  PubMed  Google Scholar 

  • Cordell HJ (2002) Epistasis: what it means, what it doesn’t mean, and statistical methods to detect it in humans. Hum Mol Genet 11:2463–2468

    Article  CAS  PubMed  Google Scholar 

  • Coric V, Milanovic S, Wasylink S, Patel P, Malison R, Krystal JH (2003) Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder. Psychopharmacology 167:219–220

    CAS  PubMed  Google Scholar 

  • Cull-Candy S, Brickley S, Farrant M (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11:327–335

    Article  CAS  PubMed  Google Scholar 

  • Deckersbach T, Savage CR, Curran T, Bohne A, Wilhelm S, Baer L, Jenike MA, Rauch SL (2002) A study of parallel implicit and explicit information processing in patients with obsessive-compulsive disorder. Am J Psychiatry 159:1780–1782

    Article  PubMed  Google Scholar 

  • Di Bella D, Cavallini MC, Bellodi L (2002) No association between obsessive-compulsive disorder and the 5-HT(1Dbeta) receptor gene. Am J Psychiatry 159:1783–1785

    Article  PubMed  Google Scholar 

  • First M, Spitzer R, Gibbon M, Williams J (1996) Structured clinical interview for DSM-IV-TR axis I disorders, patient edition. (SCID-I/P, version 2.0). Biometrics Research, New York State Psychiatric Institute

  • Glatt C, Freimer N (2002) Association analysis of candidate genes for neuropsychiatric disease: the perpetual campaign. Trends Genet 18:307–312

    Google Scholar 

  • Goodman W, Price L, Rasmussen S, Mazure C, Fleishmann R, Hill C, Heninger G, Charney D (1989) The Yale-Brown obsessive-compulsive scale. I. Development, use, and reliability. Arch Gen Psychiatry 46:1006–1011

    CAS  PubMed  Google Scholar 

  • Hanna G, Veenstra-VanderWeele J, Cox N, Boehnke M, Himle J, Curtis G, Leventhal B, Cook E (2002) Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands. Am J Med Genet (Neuropsychiatr Genet) 114:541–552

    Google Scholar 

  • Hettema JM, Neale MC, Kendler KS (2001) A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 158:1568–1578

    Article  CAS  PubMed  Google Scholar 

  • Inouye E (1965) Similar and dissimilar manifestations of obsessive-compulsive neurosis in monozygotic twins. Am J Psychiatry 121:1171–1175

    CAS  PubMed  Google Scholar 

  • Klitz W, Stephen J, Grote M, Carrington M (1995) Discordant patterns of linkage disequilibrium of the peptide transporter loci within the HLA class II region. Am J Hum Genet 57:1436–1444

    CAS  PubMed  Google Scholar 

  • Krawczak M, Boehringer S, Epplen J (2001) Correcting for multiple testing in genetic association studies: the legend lives on. Hum Genet 109:566–567

    Article  Google Scholar 

  • Krystal J, Belger A, D’Souza D, Anand A, Charney D, Aghajanian G, Moghaddam B (1999) Therapeutic implications of the hyperglutamatergic effects of NMDA antagonists. Neuropsychopharmacology 21:S143–S157

    CAS  Google Scholar 

  • Lahiri D, Nurnberger J (1991) A rapid no-enzymatic method for the preparation of HMW DNA from blood for RFLP analysis. Nucleic Acids Res 19:5444

    CAS  PubMed  Google Scholar 

  • Laird N, Horvath S, Xu X (2000) Implementing a unified approach to family based tests of association. Genet Epidemiol 19:S36–S42

    Article  PubMed  Google Scholar 

  • Lander ES (1996) The new genomics: global views of biology. Science 274:536–539

    CAS  PubMed  Google Scholar 

  • Leckman J, Zhang L, Alsobrook J, Pauls D (2001) Symptom dimensions in obsessive-compulsive disorder: towards quantitative phenotypes. Am J Med Genet 105:28–30

    Article  CAS  PubMed  Google Scholar 

  • Loftis JM, Janowsky A (2003) The N-methyl-d-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications. Pharmacol Ther 97:55–85

    Article  CAS  PubMed  Google Scholar 

  • Lyoo IK, Renshaw PF (2002) Magnetic resonance spectroscopy: current and future applications in psychiatric research. Biol Psychiatry 51:195–207

    Article  PubMed  Google Scholar 

  • Macciardi F (2003) Multiple testing in genetic association studies: to correct or not to correct? Am J Med Genet 122B:31–32

    Google Scholar 

  • McGrath MJ, Campbell KM, Parks CR, Burton FH (2000) Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette’s syndrome and obsessive-compulsive disorder. Brain Res 877:23–30

    Article  CAS  PubMed  Google Scholar 

  • Miyatake R, Furukawa A, Suwaki H (2002) Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia. Mol Psychiatry 7:1101–1106

    Article  CAS  PubMed  Google Scholar 

  • Mundo E, Richter MA, Sam F, Macciardi F, Kennedy JL (2000) Is the 5-HT(1Dbeta) receptor gene implicated in the pathogenesis of obsessive-compulsive disorder? Am J Psychiatry 157:1160–1161

    Article  CAS  PubMed  Google Scholar 

  • Mundo E, Richter MA, Zai G, Sam F, McBride J, Macciardi F, Kennedy JL (2002) 5HT1Dbeta receptor gene implicated in the pathogenesis of obsessive-compulsive disorder: further evidence from a family-based association study. Mol Psychiatry 7:805–809

    Article  CAS  PubMed  Google Scholar 

  • Nestadt G, Samuels J, Riddle M, Bienvenu J, Liang K-Y, Labuda M, Walkup J, Grados M, Hoehn-Saric R (2000) A family study of obsessive-compulsive disorder. Arch Gen Psychiatry 57:358–363

    Article  CAS  PubMed  Google Scholar 

  • Nicolini H, Hanna G, Baxter L, Schwartz J, Weissbacker K, Spence M (1991) Segregation analysis of obsessive compulsive and associated disorders. Ursus Medicus 1:25–28

    Google Scholar 

  • Nishiguchi N, Shirakawa O, Ono H, Hashimoto T, Maeda K (2000) Novel polymorphism in the gene region encoding the carboxy-terminal intracellular domain of the NMDA receptor 2B subunit: analysis of association with schizophrenia. Am J Psychiatry 157:1329–1331

    Article  CAS  PubMed  Google Scholar 

  • Nordstrom EJ, Burton FH (2002) A transgenic model of comorbid Tourette’s syndrome and obsessive-compulsive disorder circuitry. Mol Psychiatry 7:617–625

    Article  CAS  PubMed  Google Scholar 

  • Nyholt D (2001) Genetic case-control association studies—correcting for multiple testing. Hum Genet 109:564–565

    Google Scholar 

  • Ohtsuki T, Sakurai K, Dou H, Toru M, Yamakawa-Kobayashi K, Arinami T (2001) Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia. Mol Psychiatry 6:211–216

    Article  CAS  PubMed  Google Scholar 

  • Pato M, Pato C, Pauls D (2002) Recent findings in the genetics of OCD. J Clin Psychiatry 63:30–33

    PubMed  Google Scholar 

  • Pauls D (2001) The genetics of obsessive-compulsive disorder. Fifth International Obsessive Compulsive Disorder Conference, Sardinia, Italy

  • Pauls DL, Alsobrook JP 2nd, Goodman W, Rasmussen S, Leckman JF (1995) A family study of obsessive–compulsive disorder. Am J Psychiatry 152:76–84

    CAS  PubMed  Google Scholar 

  • Perneger T (1998) What’s wrong with Bonferroni adjustments. BMJ 316:1236–1238

    CAS  Google Scholar 

  • Pfleiderer B, Michael N, Erfurth A, Ohrmann P, Hohmann U, Wolgast M, Fiebich M, Arolt V, Heindel W (2003) Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients. Psychiatry Res 122:185–192

    Article  CAS  PubMed  Google Scholar 

  • Phillips KA (2002) The obsessive-compulsive spectrums. Psychiatr Clin N Am 25:791–809

    PubMed  Google Scholar 

  • Rasmussen SA, Eisen JL (1994) The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry 55:5–10; discussion 11–14

    Google Scholar 

  • Rauch S (2000) Neuroimaging research and the neurobiology of obsessive-compulsive disorder: where do we go from here? Biol Psychiatry 47:168–170

    Article  CAS  PubMed  Google Scholar 

  • Rauch SL, Savage CR, Alpert NM, Dougherty D, Kendrick A, Curran T, Brown HD, Manzo P, Fischman AJ, Jenike MA (1997) Probing striatal function in obsessive-compulsive disorder: a PET study of implicit sequence learning. J Neuropsychiatr Clin Neurosci 9:568–573

    CAS  PubMed  Google Scholar 

  • Rauch S, Whalen P, Dougherty D, Jenike M (1998) Neurobiologic models of obsessive-compulsive disorder. In: Jenike M, Baer L, Minichiello W (eds) Obsessive-compulsive disorders: practical management. Mosby, St Louis, pp 222–253

  • Rosenberg D (2002) Selective serotonin-reuptake inhibitors. In: Rosenberg D, Davanzo P, Gershon S (eds) Pharmacotherapy for child and adolescent psychiatric disorders. Dekker, New York, pp 223–296

  • Rosenberg D, Hanna G (2000) Genetic and imaging strategies in obsessive-compulsive disorder: potential implications for treatment development. Biol Psychiatry 48:1210–1222

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg D, Keshavan M (1998) Toward a neurodevelopmental model of obsessive-compulsive disorder. Biol Psychiatry 43:623–640

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg D, MacMillan S (2002) Imaging and neurocircuitry of OCD. In: Davis K, Nemeroff C, Coyle J, Charney D (eds) Neuropsychopharmacology: the 5th generation of progress. Lippincott, Williams and Wilkins, Baltimore, pp 1621–1646

  • Rosenberg D, MacMaster F, Keshavan M, Fitzgerald K, Stewart C, Moore G (2000) Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry 39:1096–1103

    Google Scholar 

  • Rosenberg D, MacMillan S, Moore G (2001) Brain anatomy and chemistry may predict treatment response in paediatric obsessive-compulsive disorder. Int J Neuropsychopharmacol 4:179–190

    Article  CAS  PubMed  Google Scholar 

  • Saint-Cyr J (2003) Frontal-striatal circuit functions: context, sequence, and consequence. J Int Neuropsychol Soc 9:103–127

    Article  PubMed  Google Scholar 

  • Schiffer HH (2002) Glutamate receptor genes: susceptibility factors in schizophrenia and depressive disorders? Mol Neurobiol 25:191–212

    Article  PubMed  Google Scholar 

  • Veenstra-VanderWeele J, Kim SJ, Gonen D, Hanna GL, Leventhal BL, Cook EH Jr (2001) Genomic organization of the SLC1A1/EAAC1 gene and mutation screening in early-onset obsessive-compulsive disorder. Mol Psychiatry 6:160–167

    Article  CAS  PubMed  Google Scholar 

  • Williams N, Bowen T, Spurlock G, Norton N, Williams H, Hoogendoorn B, Owen M, O’Donovan M (2002) Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-d-aspartate glutamate receptor. Mol Psychiatry 7:508–514

    Article  CAS  PubMed  Google Scholar 

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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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  • DOI: https://doi.org/10.1007/s00213-004-1847-1

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