Association Analysis Of N-methyl-D-aspartate Pathway Related Gene Polymorphisms With Early-onset Schizophrenia In Han Chinese Population

Objective:Early-onset schizophrenia was defined as schizophrenia with onset before the age of 18 according to the previous literature and it may be related to glutamate dysfunction. NMDA pathway related gene mutation may lead to glutamate dysfunction. So this study aimed to investigate the association between NMDA pathway genes(DAOA: rs2391191,NOS1AP: rs348624, rs12742393, rs1415263, DISC1: rs1000731,rs821633, GSK3B: rs6438552) polymorphisms with early-onset schizophrenia, and to explore the role of gene-gene interaction on the pathogenesis of schizophrenia.Methods:1. 153 early-onset schizophrenia trios(including 153 EOS and 306 biological parents) were genotyped by Taqman genotyping assay. H-W equilibrium and association study was conducted using Haploview software. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction(GMDR) software.2. To verify the topranked marker in expanded samples of 288 EOS,491 non early-onset schizophrenia patients and 872 healthy controls using Taqman genotyping assay. H-W equilibrium and association study was analysed using SHEsis software. The relevance between the topranked marker and onset age of schizophrenia were analysed using Kaplan-Meier survival analysis.3. NOS1 AP m RNA expression levels were examed in 50first-episode schizophrenic patients and 50 healthy controls using Taqman RT-PCR in peripheral blood. NOS1 AP protein expression levels were examed in 22 first-episode schizophrenic patients and 58 healthy controls using ELISA in peripheral blood.Results:1. The mean onset age of 153 early-onset schizophrenia(including81 males, 72 females) was 13.94±2.94 years old. NOS1 AP rs12742393was significant associated with schizophrenia(P = 0.03) after FDR correction. The GMDR analysis showed a significant gene-gene interaction among rs348624, rs12742393, rs1415263, rs821633,rs1000731, rs2391191 and rs6438552(P = 0.00).2.There was a significant difference in allele and genotype frequencies of rs12742393(?2 = 8.22, df = 1, P = 0.00; ?2 = 8.66, df = 2, P= 0.01) between EOS and healthy control. Survival analysis showed that the rs12742393 risk alleles(C) was significantly related to onset age in SCZ(P < 0.05).3. The age and sex was matched between first-episode SCZ patients and healthy control. There are significant differences in the NOS1 AP m RNA and protein expression levels of peripheral blood between schizophrenia and healthy controls(P = 0.00).Conclusions: The present study provided suggestive evidence that the rs12742393 was significantly associated with early-onset schizophrenia in Han Chinese population. A statistical epistatic interaction between NOS1 AP, DISC1, DAOA and GSK3 B was detected.