Genetic Association Study of Mismatch Negativity and NMDA Receptor Genes in Schizophrenia
Date Issued
2011
Date
2011
Author(s)
Lin, Yi-Ting
Abstract
Background
Mismatch negativity (MMN) is an auditory event-related potential and is related to the N-methyl-D-aspartic acid (NMDA) receptor function. The NMDA receptor system dysfunction is a core pathology of schizophrenia. MMN deficit is a robust neurophysiological feature in chronic schizophrenia, with effect size around 0.99. It is also a candidate endophenotype for schizophrenia and may be useful for the association analysis of this complex genetic disorder. In this study, we hypothesized that (1) NMDA receptor subunits genes are associated with schizophrenia, and (2) NMDA receptor subunits genes are associated with MMN.
Method
The study is a case-control single nucleotide polymorphism (SNP) association analysis. 138 schizophrenia patients and 103 healthy controls were enrolled. NMDA receptor subunit genes were GRIN1, GRIN2B, GRIN2C, GRIN2D, and GRIN3B and GRID1 were investigated. Haplotype-tagged SNPs and SNPs reported to be significantly associated with schizophrenia were genotyped by MassArray iPLEX SNP genotyping system. Both single-SNP-based and haplotype-based association analyses were conducted. To test the second hypothesis, interaction between SNP and disease status was explored first. If the interaction term was significant, separate analysis would be done in case group and control group respectively. Each nominally significant result was permuted for 10,000 times to get empirical p-value, in order to decrease the influence of multiple comparison. The epistatic effects on affected status and MMN were analyzed as well.
Results
MMN was significantly impaired in schizophrenia patients. 48 SNPs were genotyped, and 40 of them passed the quality control criteria. None of the 40 SNPs were associated with affected status. In healthy subject group, rs2240158 of GRIN3B was significantly associated with MMN in both additive model (empirical p-value 0.039) and dominant model (empirical p-value 0.013). Haplotype-based and epistatical association analysis yielded no significant result.
Conclusions
Our data didn’t support GRIN1, GRIN2B, GRIN2C, GRIN2D, GRIN3B, and GRID1 as candidate genes for schizophrenia. Rs2240158 of GRIN3B was significantly associated with MMN in healthy subjects. The functional significance and the association with MMN need further studies.
Subjects
mismatch negativity
schizophrenia
glutamate
NMDA receptor
association analysis
single nucleotide polymorphism
Type
thesis
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