Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder

doi:doi:10.1038/sj.mp.4001218

Molecular Psychiatry (2003) 8, 241–245. doi:10.1038/sj.mp.4001218

Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder

E Mundo^1,2, S Tharmalingham¹, M Neves-Pereira¹, E J Dalton¹, F Macciardi¹, S V Parikh³, A Bolonna⁴, R W Kerwin⁴, M J Arranz⁴, A J Makoff⁴ and J L Kennedy¹

¹Neurogenetics Section, Centre for Addition and Mental Health (CAMH), Department of Psychiatry, University of Toronto, Toronto ON, Canada
²Department of Psychiatry and Department of Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy
³Bipolar Disorders Clinic, CAMH, Department of Psychiatry, University of Toronto, Toronto ON, Canada
⁴Department of Psychological Medicine, Institute of Psychiatry, University of London, London, UK

Correspondence: Dr JL Kennedy, Head, Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Clarke Site R-31, Toronto, ON Canada M5T 1R8. E-mail: james_kennedy@CAMH.net

Received 18 February 2002; Revised 21 June 2002; Accepted 26 June 2002.

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Abstract

There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (²=4.765, df=1, P=0.030 and ²= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global ²=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.