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Open Access Research article

Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1 genes

Emilio Sacchetti123, Catia Scassellati4, Alessandra Minelli5, Paolo Valsecchi12, Cristian Bonvicini4, Patrizio Pasqualetti6, Alessandro Galluzzo12, Rosaria Pioli7 and Massimo Gennarelli45*

Author Affiliations

1 Psychiatric Unit, University of Brescia, School of Medicine, Viale Europa 11, Brescia, 25123, Italy

2 Department of Mental Health, Brescia Spedali Civili, Brescia, Italy

3 Center of Behavioral and Neurodegenerative Disorders, Brescia University and EULO, Brescia, Italy

4 Genetic Unit, I.R.C.C.S. “San Giovanni di Dio” – Fatebenefratelli, Via Pilastroni 4, Brescia, 25125, Italy

5 Department of Molecular and Translational Medicine, Division of Biology and Genetics, Viale Europa 11, Brescia, 25123, Italy

6 AFaR, Department of Neuroscience, Hospital Fatebenefratelli Isola Tiberina, Rome, 00186, Italy

7 Psychitric Unit, I.R.C.C.S. “San Giovanni di Dio” - Fatebenefratelli, Brescia, Italy

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BMC Medical Genetics 2013, 14:33  doi:10.1186/1471-2350-14-33

Published: 9 March 2013

Abstract

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 (pcorrect = 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 (pcorrect = 0.02, pcorrect = 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 (pcorrect = 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.

Keywords:
tagSNPs; Schizophrenia; Glutamate neurotransmission; DAO; DAOA; PPP3CC; DTNBP1; Association study; Phenotypic dissection