The post-synaptic density royal nomadic 5413 rug (PSD) of glutamatergic synapses harbors a multitude of proteins critical for maintaining synaptic dynamics.Alteration of protein expression levels in this matrix is a marked phenomenon of neuropsychiatric disorders including schizophrenia, where cognitive functions are impaired.To investigate the genetic relationship of genes expressed in the PSD with schizophrenia, a family-based association analysis of genetic variants in PSD genes such as DLG4, DLG1, PICK1 and MDM2, was performed, using Japanese samples (124 pedigrees, n = 376 subjects).Results showed a significant association of the rs17203281 variant from the DLG4 gene, with preferential transmission of the C allele (p = 0.
02), although significance disappeared after correction for multiple testing.Replication analysis of this variant, found no association in a Chinese schizophrenia cohort (293 pedigrees, n = 1163 subjects) or in a Japanese case-control sample (n = 4182 subjects).The DLG4 expression levels between postmortem brain samples from schizophrenia patients showed no significant changes from controls.Interestingly, a five marker haplotype in DLG4, involving rs2242449, rs17203281, rs390200, rs222853 and rs222837, was enriched in a population specific manner, where the sequences A-C-C-C-A and G-C-C-C-A accumulated e. cuarenta cerveza in Japanese (p = 0.
0009) and Chinese (p = 0.0007) schizophrenia pedigree samples, respectively.However, this could not be replicated in case-control samples.None of the variants in other examined candidate genes showed any significant association in these samples.
The current study highlights a putative role for DLG4 in schizophrenia pathogenesis, evidenced by haplotype association, and warrants further dense screening for variants within these haplotypes.