Although many major breakthrough had identificated potential susceptibility genes for schizophrenia, the aetiology of schizophrenia is still unknown. In the present study, we focused on the N-methyl-Daspartate receptors related genes nitric oxide synthase 1 adaptor gene (NOS1AP), disrupted in schizophrenia 1 gene (DISC1), d-amino acid oxidase activator gene (DAOA), and glycogen synthase kinase 3-beta gene (GSK3B). A family-based genetic association study (459 Han Chinese subjects in 153 nuclear families) using 3 single nucleotide polymorphisms in NOS1AP, 2 in DISC1, 1 in DAOA and 1 in GSK3B was conducted. We found rs12742393 have just positive trend with schizophrenia (SCZ) (p = 0.07) after FDR correction. NOS1AP mRNA and serum levels were significantly elevated in SCZ patients (p < 0.001; p < 0.001) compared with healthy control. However, expression Quantitative Trait Loci (eQTL) analysis have demonstrated that rs12742393 genotype were not significantly associated with the NOS1AP mRNA expression. GMDR identified a significant seven-locus interaction model involving (NOS1AP-rs348624, rs12742393, rs1415263, DISC1-rs821633, rs1000731, DAOA-rs2391191and GSK3B- rs6438552) with a good testing accuracy (0.72). Our finding suggested statistically significant role of interaction of NOS1AP, DISC1, DAOA, and GSK3B polymorphisms (NOS1AP-rs348624, rs12742393, rs1415263, DISC1-rs821633, rs1000731, DAOA-rs2391191and GSK3B-rs6438552) in EOS susceptibility.