title: Role of the DLGAP2 gene encoding the SAP90/PSD-95-associated protein 2 in schizophrenia.
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.
authors.affiliation: Department of Psychiatry, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan.
authors.forename: Jun-Ming
authors.initials: JM
authors.lastname: Li
authors.affiliation: Department of Psychiatry, Hualien Armed Forces General Hospital, Hualien, Taiwan.
authors.forename: Chao-Lin
authors.initials: CL
authors.lastname: Lu
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
authors.forename: Min-Chih
authors.initials: MC
authors.lastname: Cheng
authors.affiliation: Department of Psychiatry, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan.
authors.forename: Sy-Ueng
authors.initials: SU
authors.lastname: Luu
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Hsu
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Hu
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
authors.forename: Hsin-Yao
authors.initials: HY
authors.lastname: Tsai
authors.affiliation: Department of Psychiatry, Chang Gung Memorial Hospital at Linkou and Chang Gung University School of Medicine, Taoyuan, Taiwan.
authors.forename: Chia-Hsiang
authors.initials: CH
authors.lastname: Chen
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013624:Taiwan
chemical_list: C413124:DLGAP2 protein, human; D009419:Nerve Tissue Proteins