title: Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1 genes.
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.
authors.affiliation: Psychiatric Unit, University of Brescia, School of Medicine, Viale Europa 11, 25123 Brescia, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Sacchetti
authors.forename: Catia
authors.initials: C
authors.lastname: Scassellati
authors.forename: Alessandra
authors.initials: A
authors.lastname: Minelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Valsecchi
authors.forename: Cristian
authors.initials: C
authors.lastname: Bonvicini
authors.forename: Patrizio
authors.initials: P
authors.lastname: Pasqualetti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Galluzzo
authors.forename: Rosaria
authors.initials: R
authors.lastname: Pioli
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
mesh_terms: D000328:Adult; D019703:Calcineurin / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D003605:D-Amino-Acid Oxidase / Q000235:genetics*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C475071:DAOA protein, human; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C417983:DAO protein, human; D003605:D-Amino-Acid Oxidase; D019703:Calcineurin; C525675:PPP3CC protein, human