1. ¹Centre for Addiction and Mental Health, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
2. ²Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
3. ³Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
4. ⁴Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
5. ⁵Department of Psychiatry, University of Coimbra, Portugal
6. ⁶State University of New York, Buffalo, NY, USA

Correspondence: HHM Van Tol or JL Kennedy, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada, M5T 1R8. E-mails: James_Kennedy@camh.net, hubert.van.tol@utoronto.ca

Abstract

Although the genetic contribution to schizophrenia is substantial, positive findings in whole-genome linkage scans have not been consistently replicated. We analyzed gene expression in various rat conditions to identify novel candidate genes for schizophrenia. Suppression subtraction hybridization (SSH), with polyA mRNA from temporal and frontal cortex of rats, was used to identify differentially expressed genes. Expression of mRNA was compared between adult Lewis and Fischer 344 (F344) rats, adult and postnatal day 6 (d6) F344, and adult F344 treated with haloperidol or control vehicle. These groups were chosen because each highlights a particular aspect of schizophrenia: differences in strain vulnerability to behavioral analogs of psychosis; factors that may relate to disease onset in relation to CNS development; and improvement of symptoms by haloperidol. The 14-3-3 gene family, as represented by 14-3-3 and 14-3-3 isoforms in the SSH study, and SNAP-25 were among the candidate genes. Genetic association between schizophrenia and the 14-3-3 gene, positioned close to a genomic locus implicated in schizophrenia, and SNAP-25 genes was analyzed in 168 schizophrenia probands and their families. These findings address three different genes in the 14-3-3 family. We find a significant association with schizophrenia for two polymorphisms in the 14-3-3 gene: a 7 bp variable number of tandem repeats in the 5' noncoding region (P=0.036, 1 df), and a 3' untranslated region SNP (753G/A) that is an RFLP visualized with Ava II (P=0.028). There was no significant genetic association with SNAP-25. The candidate genes identified may be of functional importance in the etiology, pathophysiology or treatment response of schizophrenia or psychotic symptoms. This is to our knowledge the first report of a significant association between the 14-3-3-chain gene and schizophrenia in a family-based sample, strengthening prior association reports in case–control studies and microarray gene expression studies.