Genetic and post-mortem mRNA analysis of the 14-3-3 genes that encode phosphoserine/threonine-binding regulatory proteins in schizophrenia and bipolar disorder Albert H.C. Wong a,b,c,d, * , Olga Likhodi a , Joseph Trakalo a , Muneeb Yusuf d , Anuradha Sinha a , Carlos N. Pato e,f , Michele T. Pato e,f , Hubert H.M. Van Tol a,b,c,d , James L. Kennedy a,b,d a Centre for Addiction and Mental Health, Faculty of Medicine, University of Toronto, Canada b Department of Psychiatry, Faculty of Medicine, University of Toronto, Canada c Department of Pharmacology, Faculty of Medicine, University of Toronto, Canada d Institute of Medical Science, Faculty of Medicine, University of Toronto, Canada e Upstate Medical Center, Research Division, State University of New York, Syracuse, NY, USA f VAMC, Washington, DC, USA Received 22 March 2005; received in revised form 10 June 2005; accepted 13 June 2005 Available online 27 July 2005 Abstract Background: Previous work with animal models of psychosis, human genetic studies, and human post-mortem gene expression studies implicate the 14-3-3 family of genes in schizophrenia. The 14-3-3 genes code for a family of proteins that bind to and regulate other proteins, and they modulate neurodevelopment, cell-division, signal transduction and gene transcription. Objective: To explore the role of five 14-3-3 isoforms (h, g, q, ~ , and D) in schizophrenia by: (1) comparing mRNA levels in post-mortem brain from schizophrenic, bipolar and control subjects and (2) assessing genetic association with schizophrenia in both case-control and nuclear family samples. Methods: Quantitative PCR (q-PCR) was used to determine relative mRNA levels in dorsolateral prefrontal cortex (Brod- mann’s area 46) samples donated by the Stanley Medical Research Institute (SMRI). Selected SNPs were genotyped in all five isoforms for association analysis in both family and case-control samples. Results: No significant differences in 14-3-3 mRNA expression levels between the diagnostic groups were found. A significant genetic association with schizophrenia was found for the 14-3-3~ isoform in a subset of nuclear families of British ancestry (TDT: v 2 = 7.2; df =1; p = 0.0073), in the case-control sample overall ( p =0.011), and in a subset of the case- control sample. 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.06.009 * Corresponding author. Room 711 Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada, M5T 1R8. Tel.: +1 416 535 8501x4010; fax: +1 416 979 4663. E-mail address: albert.wong@utoronto.ca (A.H.C. Wong). Schizophrenia Research 78 (2005) 137 – 146 www.elsevier.com/locate/schres