Abstract
Aberrant synaptic dysfunction is implicated in the pathogenesis of schizophrenia. The DLGAP2 gene encoding the SAP90/PSD-95-associated protein 2 (SAPAP2) located at the post-synaptic density of neuronal cells is involved in the neuronal synaptic function. This study aimed to investigate whether the DLGAP2 gene is associated with schizophrenia. We resequenced the putative promoter region and all the exons of the DLGAP2 gene in 523 patients with schizophrenia and 596 non-psychotic controls from Taiwan and conducted a case-control association analysis. We identified 19 known SNPs in this sample. Association analysis of 9 SNPs with minor allele frequency greater than 5% showed no association with schizophrenia. However, we found a haplotype (CCACCAACT) significantly associated with schizophrenia (odds ratio:2.5, p<0.001). We also detected 16 missense mutations and 1 amino acid-insertion mutation in this sample. Bioinformatic analysis showed some of these mutations were damaging or pathological to the protein function, but we did not find increased burden of these mutations in the patient group. Notably, we identified 5 private rare variants in 5 unrelated patients, respectively, including c.−69+9C>T, c.−69+13C>T, c.−69+47C>T, c.−69+55C>T at intron 1 and c.−32A>G at untranslated exon 2 of the DLGAP2 gene. These rare variants were not detected in 559 control subjects. Further reporter gene assay of these rare variants except c.−69+13C>T showed significantly elevated promoter activity than the wild type, suggesting increased DLGAP2 gene expression may contribute to the pathogenesis of schizophrenia. Our results indicate that DLGAP2 is a susceptible gene of schizophrenia.
Highlights
Schizophrenia is a common and often debilitating mental disorder characterized by hallucination, delusion, bizarre thinking that affects approximately 1% of the general population worldwide
As far as the pathogenesis of schizophrenia is concerned, increasing evidence demonstrates that aberrant synaptogenesis and synaptic dysfunction play an important role in the pathophysiology of schizophrenia, genes involved in the structural and functional integrity of synapse are considered as potential candidate genes of schizophrenia [4,5,6,7]
Further haplotype-based association analysis derived from these 9 SNPs showed a significant difference in the haplotype distribution of CCACCAACC, CCACCAACT, and CGGCAAACT between the schizophrenic patients and controls, but only haplotype CCACCAACT remained significantly associated with schizophrenia after Monte Carlo permutation test (Table 2)
Summary
Schizophrenia is a common and often debilitating mental disorder characterized by hallucination, delusion, bizarre thinking that affects approximately 1% of the general population worldwide. Several studies have demonstrated that the DLGAP gene family is involved the pathophysiology of various psychiatric disorders. Serial studies supported that the DLGAP3 gene is a promising functional candidate for Tourette syndrome and obsessive compulsive disorder [9,10,11,12]. Our team has identified a private rare mutation (c.1922A.G) of the DLGAP1 gene, which changes lysine to arginine at codon 641 (K641R) in one out of 121 schizophrenia, but not in 275 non-psychotic control subjects [14]. Our serial genetic studies of schizophrenia lend support to a hypothesis that schizophrenia specific rare variants in DLGAP gene family may be involved the genetic pathophysiology of schizophrenia
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