title: Genetic and functional analysis of the gene encoding GAP-43 in schizophrenia.
abstract: OBJECTIVE
  In earlier reports, growth-associated protein 43 (GAP-43) has been shown to be critical for initial establishment or reorganization of synaptic connections, a process thought to be disrupted in schizophrenia. Additionally, abnormal GAP-43 expression in different brain regions has been linked to this disorder in postmortem brain studies. In this study, we investigated the involvement of the gene encoding GAP-43 in the susceptibility to schizophrenia.
  
  
  METHODS
  We searched for genetic variants in the promoter region and 3 exons (including both UTR ends) of the GAP-43 gene using direct sequencing in a sample of patients with schizophrenia (n=586) and non-psychotic controls (n=576), both being Han Chinese from Taiwan, and conducted an association and functional study.
  
  
  RESULTS
  We identified 11 common polymorphisms in the GAP-43 gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. Additionally, we identified 4 rare variants in 5 out of 586 patients, including 1 variant located at the promoter region (c.-258-4722G>T) and 1 synonymous (V110V) and 2 missense (G150R and P188L) variants located at exon 2. No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated that the regulatory activity of construct containing c.-258-4722T was significantly lower as compared to the wild type construct (c.-258-4722G; p<0.001). In silico analysis also demonstrated the functional relevance of other rare variants.
  
  
  CONCLUSIONS
  Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and it provides genetic clues that indicate the involvement of GAP-43 in this disorder.
authors.affiliation: Department of Psychiatry, Tzu Chi General Hospital, Hualien, Taiwan. cchen@nhri.org.tw
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Shen
authors.forename: Ho-Min
authors.initials: HM
authors.lastname: Tsai
authors.forename: Min-Chih
authors.initials: MC
authors.lastname: Cheng
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Hsu
authors.forename: Shih-Fen
authors.initials: SF
authors.lastname: Chen
authors.forename: Chia-Hsiang
authors.initials: CH
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D005091:Exons / Q000235:genetics; D005260:Female; D019922:GAP-43 Protein / Q000235:genetics*; D015870:Gene Expression; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009447:Neuroblastoma / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000235:genetics*; D014162:Transfection
chemical_list: D019922:GAP-43 Protein