Association between the NMDA glutamate receptor GRIN2B gene and obsessive–compulsive disorder

Association between the NMDA glutamate receptor GRIN2B gene and obsessive–compulsive disorder

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J Psychiatry Neurosci 2012;37(4):273-81

Pino Alonso, PhD;* Mónica Gratacós, PhD;* Cinto Segalàs, PhD; Georgia Escaramís, PhD; Eva Real, MD; Mónica Bayés, PhD; Javier Labad, MD; Clara López-Solà, MD; Xavier Estivill, PhD; José M. Menchón, PhD

Alonso, Segalàs, Real, López-Solà, Menchón — OCD Clinical and Research Unit, Psychiatry Department, Hospital Universitari de Bellvitge, Barcelona, Spain; Alonso, Segalàs, Real, López-Solà, Menchón — Centro de Investigación en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Spain; Alonso, Menchón — Department of Clinical Sciences, Bellvitge Campus, University of Barcelona, Barcelona, Spain; Gratacós, Escaramís, Estivill — CIBERESP en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, and the Genes and Disease Program, Center for Genomic Regulation, Barcelona Biomedical Research Park, Barcelona, Spain; Real — Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain; Bayés, Estivill — Genomics Core Facility and Centro Nacional de Genotipado (CeGen), Center for Genomic Regulation (CRG), Barcelona, Spain; Labad — Hospital Psiquiatric Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain; Estivill — Experimental and Health Sciences Department, Pompeu Fabra University, Barcelona, Spain

*These authors contributed equally to this work.

Abstract

Background: Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neuro transmission in the pathogenesis of obsessive–compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes.

Methods: Between 2003 and 2008, we performed a case–control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′ UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions.

Results: We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37–4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22–3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions.

Limitations: Study limitations included the risk of population stratification associated with the case–control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3′ UTR and exon 13 of GRIN2B.

Conclusion: Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder.


Presented as a poster at the XVIII World Congress on Psychiatric Genetics in Athens, Greece, Oct. 3–7, 2010.

Submitted Aug. 17, 2011; Revised Nov. 14, Dec. 3, 14, 2011; Accepted Dec. 20, 2011.

Acknowledgements: We thank the study participants and the staff from Department of Psychiatry at Hospital de Bellvitge who helped us with the recruitment of participants. We thank Michael Maudsley from the Linguistic Services of University of Barcelona for revising the manuscript. Financial support was received from the Psychiatric Genetics Network (G03/184), the Spanish Ministry of Health, Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias de la Seguridad Social (PI10/01753, PI10/01003, CIBER-CB06/03/0034, CIBERESP), Barcelona node of the Spanish National Genotyping Center (CEGEN) and Genome Spain.

Competing interests: As above for P. Alonso, C. Segalà, E. Real and J.M.Menchón. None declared for all other authors.

Contributors: P. Alonso, M. Gratacós and J.M. Menchón designed the study. P. Alonso, M. Gratacós, C. Segalàs, E. Real, J. Labad and C. López-Solà acquired the data, which P. Alonso, M. Gratacós, G. Escaramís, M. Bayés, X. Estivill and J.M. Menchón analyzed. P. Alonso and M. Gratacós wrote the article. All authors reviewed the article and approved its publication.

DOI: 10.1503/jpn.110109

Correspondence to: P. Alonso, OCD Clinical and Research Unit, Department of Psychiatry, Bellvitge University Hospital, C/Feixa Llarga s/n, 08907, L’Hospitalet de Llobregat, Barcelona, Spain; mpalonso@bellvitgehospital.cat