Role of the <i>DLGAP2</i> Gene Encoding the SAP90/PSD-95-Associated Protein 2 in Schizophrenia

<div><p>Aberrant synaptic dysfunction is implicated in the pathogenesis of schizophrenia. The <i>DLGAP2</i> 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 <i>DLGAP2</i> gene is associated with schizophrenia. We resequenced the putative promoter region and all the exons of the <i>DLGAP2</i> 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 <i>DLGAP2</i> 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 <i>DLGAP2</i> gene expression may contribute to the pathogenesis of schizophrenia. Our results indicate that <i>DLGAP2</i> is a susceptible gene of schizophrenia.</p>