The Transmission Disequilibrium Analysis Between NMDAR1 Gene Polymorphisms And Bipolar

Background and Objective:Bipolar disorder (bipolar affective disorder) is characterized by marked mood swings between mania (mood elevation) and bipolar depression that cause significant personal distress or social dysfunction, and are not caused by drugs or known physical disorder. The cause of bipolar disorder is uncertain. Studying the cause and genetic mechanisms is a challenge in psychiatry. Family and twin studies suggest a genetic basis in bipolar. First degree relatives of bipolar patients have a 10 times greater risk of developing the illness than the general population. And the heritability is high at around 80%. However, the mode of genetics is not clear. The genetic basis of bipolar disorder probably involves multiple genes interacting with each other and with environmental components in as-yet mysterious ways.The gene studies in bipolar have focused mainly on genes coding for the serotonin and dopamine receptors. The amino acid glutamate has been hypothesized to be implicated in the pathogenesis of major psychoses, and a model involving glutamatergic deficiency has been proposed for schizophrenia. N-methyl-D-aspartate receptor is one of the glutamate receptors activated by the NMDA. NMDAR1 is the key subunit of NMDAR, and is encoded by a gene located on chromosome 9q34.3.The antagonists of NMDAR (eg. phencyclidine and ketamine) have been found to induce cognitive and behavioral symptoms, including psychotic symptoms in humans. Particularly interesting with respect to BP are the data on the mechanism of action of the most commonly used compounds for the long-term treatment of the disease, namely lithium and valproate. There is good evidence that lithium acts via the NMDAR, either by stimulating glutamate release and inositol 1, 4, 5-triphosphatase accumulation or by inhibiting the NMDAR-mediated calcium influx. There is also evidence that valproate increases gamma-amino-butyric-acid (GABA) synthesis and release and attenuates the neuronal excitation induced by NMDA-type glutamate receptors. These findings suggest a role for the genes coding for the NMDAR as candidate genes for BP. Mundo and his colleagues collected 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents and tested for the presence of linkage disequilibrium between the NMDAR1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. For the 1001-G/C and the 6608-G/C polymorphisms, they found a preferential transmission of the G allele to the affected individuals. The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP. Livia tested three genetic polymorphisms: G-200T (5VUTR), A5806C and T5988C (both 3VUTR) in 180 matched schizophrenia case–control pairs, 86 schizophrenia nuclear family trios, and 318 bipolar disorder trios (of which 158 probands had psychotic symptoms).They detected genetic association between T5988C and bipolar disorder, and between A5806C and bipolar disorder with psychotic symptoms. The T–C–C haplotype was transmitted more frequently with bipolar disorder, but less often with schizophrenia, while the G–C–T haplotype was transmitted more often in schizophrenia. Liu Min selected 2 single nucleotide polymorphisms in NMDAR1(rs2301363 and hcv1840191)and made SNPs analysis in 100 unrelated cases and 100 controls by TaqMan. Then they compared genotypes diferences between cases an d controls. The significant results showed that the SNPs in NMDAR1 gene were related to the BP. In addition, the combined haplotype T/G had a significant diference in the two groups.These results indicated that the NMDAR1 and NMDAR2 gene confers susceptibility to bipolar disorder. So, we collected bipolar trios consist of the affected offsprings in Chinese people and selected the 1001-G/C polymorphism on NMDAR1 genes to study the association for NMDAR1 gene polymorphisms and bipolar.Objects and Methods:A total of 86 CCMD-3 bipolar probands with their living parents were studied. Genomic DNA was extracted from whole blood. We genotyped the 1001-G/C polymorphisms of the NMDAR1 gene by PCR technology and endonuclease digestion. The Hardy-Weinberg (H-W) equilibrium was tested for genotype frequency distributions. The haplotype-based haplotype relative risk (HHRR) test and the transmission disequilibrium test (TDT) were applied to detect allelic association between 1001-G/C polymorphisms and bipolar. Results:1. The Hardy-Weinberg equilibrium testThe genotype frequency distributions of all subjects were not deviated from the H-W equilibrium (P>0.05), which indicates these samples were suitable for the genetic analysis.2. The TDT analysisThe TDT analysis showed that the presence of linkage disequilibrium between the 1001-G/C, polymorphisms and bipolar (P=0.024). We found a preferential transmission of the G allele to the affected individuals. These findings suggest a role of the 1001G variants of the NMDAR1 in conferring susceptibility to bipolar. Nonetheless, the possibility that the 1001C and the variants play a protective role should also be considered.3. The HHRR analysisThe HHRR analysis suggested an allelic association between 1001-G/C and bipolar (P=0.025). This finding was consistent with TDT result.Our findings are consistent with those of Mundo's study about NMDAR1 gene and bipolar to some extent. The results indicate the presence of significant linkage disequilibrium between the 1001-G/C polymorphisms of the NMDAR1 gene and BP. If these results are replicated, there could be important implications for the involvement of the NMDAR1 gene in the pathogenesis of BP. These findings are very important not only for elucidating the molecular genetic mechanisms of bipolar, but also for genetic diagnosis, developing new drugs and prediction of bipolar.