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Background  Recent studies supported associations between four NMDA-receptor-mediated signalling genes (D-amino acid oxidase,  DAO;  D-amino acid oxidase activator,  DAOA;  protein phosphatase 3 catalytic subunit gamma isoform,  PPP3CC;  dystrobrevin-binding protein 1,  DTNBP1 ) and schizophrenia susceptibility, even though with contrasting results.    Methods  In an attempt to replicate these findings for the first time in an Italian population, a panel of 32 tagSNPs was analysed in a representative case-control sample involving 879 subjects.    Results  An association in the allele frequency was observed for the estimated  PPP3CC  CAG triplotype in the SNP window rs4872499 T/C-rs11780915 A/G-rs13271367 G/A (p correct  = 0.001). Similarly, the clustered genotype frequencies of the estimated/phased CAG triplotype differed between cases and controls (p = 0.004), with the carriers having a higher frequency in the control population (p = 0.002, odd ratio OR = 0.59, 95% confident interval CI: 0.43-0.82).  Following the phenotypic dissection strategy, the analysis of single SNPs evidenced a protective effect in males of rs11780915 and rs13271367 in  PPP3CC  gene (p correct  = 0.02, p correct  = 0.04 respectively). Moreover the estimated/phased GT diplotype (rs2070586A/G-rs3741775G/T) carriers of the  DAO  gene were more highly represented in female controls (p = 0.017, OR = 0.58, 95% CI: 0.37-0.90), as were the estimated/phased CAG triplotype carriers of the  PPP3CC  gene in females (p = 0.01, OR = 0.53 ,  95% CI: 0.32-0.87). In addition, we performed an interaction analysis, and a 66% (p = 0.003, OR = 0.34, 95% CI: 0.17-0.70) lower risk of developing schizophrenia for female (CAG + GT) carriers versus non-CAG or -GT carriers was observed. For  DTNBP1 , we found a protective effect in males for the rs6459409 (p correct  = 0.02) and the estimated/phased CT diplotype (rs6459409-rs9476886) carriers (p = 3x10 -4  ,  OR = 0.46 ,  95% CI: 0.30-0.70).  In relation to diagnostic subtypes, the estimated/phased  DAO  GT diplotype and  PPP3CC  CAG triplotype female carriers were found to show relative risk ratio (RRR) values of 0.52 and 0.54 lower risk for a paranoid phenotype respectively.    Conclusions  Although the results are preliminary and needed replication in a larger sample, this study suggests that NMDA receptor-mediated signalling genes ( DAO, PPP3CC, DTNBP1 ) might be involved in schizophrenia pathogenic mechanisms related to gender.

Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1genes