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 (χ2=4.765, df=1, P=0.030 and χ2= 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 χ2=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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders, 4th Ed. Text Revision (DSM-IV-TR). American Psychiatric Association: Washington, DC, 2000.
Craddock N, Jones I . Genetics of bipolar disorder. J Med Genet 1999; 36: 585–59.
McGuffin P, Katz R . The genetics of depression and manic-depressive disorder. Br J Psychiatry 1989; 155: 294–304.
Nurnberger Jr JI, Gershon ES . Genetics. In: Paykel ES (ed). Handbook of Affective Disorders. Churchill Livingstone: London, 1992, pp 131–148.
Meltzer H . Serotonergic dysfunction in depression. Br J Psychiatry 1989; 8 (Suppl): 25–31.
Owens MJ, Nemeroff CB . Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994; 40: 288–295.
Peroutka SJ . Serotonin receptors subtypes. Their evolution and clinical relevance. CNS Drugs 1995; 4: 18–28.
Diehl D, Gershon S . The role of dopamine in mood disorders. Compr Psychiatry 1992; 2: 115–120.
Souery D, Lipp O, Mahieu B, Mendelbaum K, De Martelaer V, Van Broeckhoven C et al. Association study of bipolar disorder with candidate genes involved in catecolamine neurotransmission: DRD2, DRD3, DAT1, and TH genes. Am J Med Genet 1996; 67: 551–555.
Oruc L, Verheyen GR, Furac I, Jakovljevic M, Ivezic S, Raeymaekers P et al. Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder. Am J Med Genet 1997; 74: 504–506.
Zhang HY, Ishigaki T, Tani K, Chen K, Shih JC, Miyasato K et al. Serotonin 2A receptor gene polymorphism in mood disorders. Biol Psychiatry 1997; 41: 768–773.
Furlong RA, Ho L, Rubinsztein JS et al. No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behavior in major affective disorder. Am J Med Genet 1998; 81: 245–247.
Esterling LE, Yoshikawa T, Turner G, Badner JA, Bengel D, Gershon ES et al. Serotonin transporter (5HTT) gene and bipolar affective disorder. Am J Med Genet 1998; 81: 37–40.
Vincent JB, Masellis M, Lawrence J, Choi V, Gurling HMD, Phil M et al. Genetic association analysis of serotonin system genes in bipolar affective disorders. Am J Psychiatry 1999; 156: 136–138.
Kirov G, Jones I, McCandless F, Craddock N, Owen MJ . Family-based association studies of bipolar disorder with candidate genes involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3, and DRD5. Mol Psychiatry 1999; 4: 558–565.
Mundo E, Walker M, Tims H, Macciardi F, Kennedy JL . Lack of linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and Bipolar Disorder. Am J Med Genet 2000; 96: 379–383.
Carlsson A, Hansson LO, Waters N, Carlsson ML . A glutamatergic deficiency model of schizophrenia. Br J Psychiatry 1999; 37: 2–6.
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.
Breier A, Malhora AK, Pinals DA, Weisenfeld NI, Pickar D . Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 1997; 154: 805–811.
Dixon JF, Los GV, Lowell EH . Lithium stimulates glutamate ‘release’ and inositol 1,4,5-trisphosphate accumulation via activation of the N-methyl-D-aspartate receptor in monkey and mouse cerebral cortex slices. Proc Natl Acad Sci USA 1994; 91: 8358–8362.
Nonaka S, Hough CJ, Chuang D . Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. Proc Natl Acad Sci USA 1998; 95: 2642–2647.
Loscher W . Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol 1999; 58: 31–59.
Nishiguchi N, Shirakawa O, Ono H, Hashimoto T, Maeda K . Novel polymorphism in the gene region encoding the carboxyl-terminal intracellular domain of the NMDA receptor 2B subunit: analysis of association with schizophrenia. Am J Psychiatry 2000; 57: 1329–1331.
Collins C, Duff C, Duncan AM, Planells-Cases R, Sun W, Norremolle A et al. Mapping of the human NMDA receptor subunit (NMDAR1) and the proposed NMDA receptor glutamate-binding subunit (NMDARA1) to chromosomes 9q34.3 and chromosome 8, respectively. Genomics 1993; 17: 237–239.
Bolonna AA, Munro J, Arranz MJ, Makoff AJ, Kerwin RW . Investigation of polymorphisms in the NMDAR1 gene in association with schizophrenia. Am J Hum Genet 1999; 65 (Suppl 4): A265.
Mundo E, Tharmalingham S, Walker M, Bolonna AA, Kerwin RW, Macciardi F et al. Linkage disequilibrium between the NMDAR1 gene and Bipolar Disorder. Am J Hum Genet 2000; 67 (Suppl 2): 356.
Lahiri DK, Nurnberger JI . A rapid no-enzymatic method for the preparation of HMW DNA from blood for RFLP analysis. Nucl Acids Res 1991; 9: 5444.
Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.
Chiano MN, Clayton DG . Fine genetic mapping using haplotype analysis and the missing data problem. Ann Hum Genet 1998; 62(Pt 1): 55–60.
Li T, Ball D, Zhao J, Murray RM, Liu X, Sham PC et al. Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 2000; 5: 77–84.
McGinnis R . General equations for Pt, Ps, and the power of the TDT and the Affected-Sib-Pair Test. Am J Hum Genet 2000; 67: 1340–1347.
Risch N, Merikangas K . The future of genetic studies on complex human diseases. Science 1996; 273: 1516–1517.
Arranz M, Collier D, Sodhi M, Ball D, Roberts G, Price J et al. Association between clozapine response and allelic variation in 5HT-2A receptor gene. Lancet 1995; 346: 281–282.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mundo, E., Tharmalingham, S., Neves-Pereira, M. et al. Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder. Mol Psychiatry 8, 241–245 (2003). https://doi.org/10.1038/sj.mp.4001218
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4001218
Keywords
This article is cited by
-
Assessment of glutamatergic synaptic transmission and plasticity in brain slices: relevance to bioelectronic approaches
Bioelectronic Medicine (2019)
-
Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces
Scientific Reports (2017)
-
Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders
Neuropsychopharmacology (2017)
-
Gene expression profiling predicts pathways and genes associated with Parkinson’s disease
Neurological Sciences (2016)
-
ENU-mutagenesis mice with a non-synonymous mutation in Grin1 exhibit abnormal anxiety-like behaviors, impaired fear memory, and decreased acoustic startle response
BMC Research Notes (2013)