Abstract
The post-synaptic density (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 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.
Highlights
Schizophrenia is a serious psychiatric disorder, with high heritability and a worldwide lifetime risk of approximately one percent [1]
The role of glutamergic receptors in schizophrenia pathogenesis is strengthened by the findings that administering NMDA receptor antagonists can induce psychotic symptoms in human and the aberrant receptor gene expression patterns observed in schizophrenia brain samples [7,8,9]
The dynamics of glutamate receptor trafficking to the postsynaptic membrane is affected by a series of scaffold proteins present in the protein-dense excitatory post synapses, known as the postsynaptic density (PSD)
Summary
Schizophrenia is a serious psychiatric disorder, with high heritability and a worldwide lifetime risk of approximately one percent [1]. Dysfunction in the glutamergic system, through the glutamate receptor which mediates excitatory neurotransmission in the central nervous system, has been implicated in the development of schizophrenia. The dynamics of glutamate receptor trafficking to the postsynaptic membrane is affected by a series of scaffold proteins present in the protein-dense excitatory post synapses, known as the postsynaptic density (PSD). The PSD comprises cell-adhesion proteins, cytoskeletal proteins, scaffolding and adaptor proteins, membrane-bound receptors and channels, G-proteins and modulators and signaling molecules, such as kinases and phosphatases [10]. The well characterized scaffolding proteins within the PSD include PDZ [PSD95 (post-synaptic density protein 95)/DLG/ ZO1] domain containing members of the PSD95 family, members of the AKAP (A-kinase anchoring protein) family, Homer family, SAPAP (SAP90/PSD95-associated protein) family and Shank (SH3 and multiple ankyrin repeat domain) family [11]
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