An association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray

Abstract

Dysfunction of the N-methyl-D-aspartate (NMDA) receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of several antagonists and on observation of genetic animal models. To conduct association analysis of the NMDA receptors in the Chinese population, we examined 16 reported SNPs across the NMDA receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B), five of which were identified in the Chinese population. In this study, we combined universal DNA microarray and ligase detection reaction (LDR) for the purposes of association analysis, an approach we considered to be highly specific as well as offering a potentially high throughput of SNP genotyping. The association study was performed using 253 Chinese patients with schizophrenia and 140 Chinese control subjects. No significant frequency differences were found in the analysis of the alleles but some were found in the haplotypes of the GRIN2B gene. The interactions between the GRIN1 and GRIN2B genes were evaluated using the multifactor-dimensionality reduction (MDR) method, which showed a significant genetic interaction between the G1001C in the GRIN1 gene and the T4197C and T5988C polymorphisms in the GRIN2B gene. These findings suggest that the combined effects of the polymorphisms in the GRIN1 and GRIN2B genes might be involved in the etiology of schizophrenia.

Repeated maternal glucocorticoid treatment affects activity and hippocampal NMDA receptor expression in juvenile guinea pigs

“…It remains to be determined whether effects extend into adulthood. This demonstration of altered behaviour and hippocampal NMDAR expression is important given that these changes have been implicated in the development of schizophrenia and cognitive impairment in humans (Qin et al 2005;Rowland et al 2005;Northoff et al 2005). That such changes are already detectable in early life may indicate potentially adverse outcomes for the psychiatric health and learning ability of children whose mothers experienced high levels of anxiety during pregnancy or were treated with repeated courses of synthetic glucocorticoid.…”

Detection of Gene × Gene Interactions in Genome-Wide Association Studies of Human Population Data

“…Examples of human diseases that have been reported to be modulated by epistatic interactions in which only one locus had a significant simple main effect include autism [58] , cervical cancer [59] , and hypertension [60] . Examples of human diseases that have been reported to be modulated by epistatic interactions in which neither locus had a significant simple main effect include Alzheimer's disease [61] , amyloid polyneuropathy [62] , atrial fibrillation [63] , breast cancer [16,64,65] , coronary heart disease [66] , dyslipidemia [67] , schizophrenia [68,69] , and type II diabetes [70] . Of these examples of the occurrence of epistatic interactions in human diseases, three-way epistatic interactions [16,[62][63] and four-way or higher-order interactions [50,63,64] have been reported.…”

Exploring the Performance of Multifactor Dimensionality Reduction in Large Scale SNP Studies and in the Presence of Genetic Heterogeneity among Epistatic Disease Models

“…The MDR methodology has been successfully applied to detecting gene-environment and gene-gene interactions for several clinical phenotypes, including: Alzheimer disease [12] , asthma [13,14] , atrial fibrillation [9,15] , myocardial infarction [16,17] , autism [18,19] , bladder cancer [20] , familial amyloid polyneuropathy [21] , hypertension [22,23] , multiple sclerosis [24] , prostate cancer [25] , schizophrenia [26] , sporadic breast cancer [10] , and type II diabetes [27] .…”