Association Between Schizophrenia and the Syntaxin 1A Gene Albert H.C. Wong, Joseph Trakalo, Olga Likhodi, Muneeb Yusuf, Antonio Macedo, Maria-Helena Azevedo, Tim Klempan, Michele T. Pato, William G. Honer, Carlos N. Pato, Hubert H.M. Van Tol, and James L. Kennedy Background: Both microarray and candidate molecule studies have demonstrated that protein and mRNA expression of syntaxin and other genes involved in synaptic function are altered in the cerebral cortex of patients with schizophrenia. Methods: Genetic association between polymorphic markers in the syntaxin 1A gene and schizophrenia was assessed in a matched case-control sample of 192 pairs, and in an independent sample of 238 nuclear families. Results: In the family-based sample, a significant genetic association was found between schizophrenia and one of the four single nucleotide polymorphisms (SNPs) tested: an intron 7 SNP (transmission disequilibrium test [TDT]  2 = 5.898; df = 1; p = .015, family-based association test [FBAT] z = 2.280, p = .023). When the results for the TDT and case-control analyses were combined, the association was stronger (n = 430; z c = 2.859; p = .004). Haplotype analysis supported the association with several significant values that appear to be driven by the intron 7 SNP. Conclusions: The results should be treated with caution until replicated, but this is the first report of a genetic association between syntaxin 1A and schizophrenia. Key Words: Schizophrenia, genetics, syntaxin 1A, synaptic protein, antipsychotics S yntaxin is a protein enriched in presynaptic terminals (Bennett et al 1992), and together with synaptosome- associated protein 25 kDa (SNAP-25) and vesicle-associ- ated membrane protein (VAMP), forms the soluble N-ethylmale- imide-sensitive factor attachment protein receptor (SNARE) complex, which is vital for chemical neurotransmission (Sollner et al 1993). Within presynaptic terminals, syntaxin binds to a host of other neurotransmitter-associated proteins, including the gamma aminobutyric acid and norepinephrine (NET) transport- ers (Quick 2002; Sung et al 2003). Syntaxin-NET binding modu- lates both the intrinsic activity of the transporter and transporter trafficking to the plasma membrane surface (Sung et al 2003). In one of the few studies of physiologic function, syntaxin was transiently downregulated in rat nucleus accumbens following administration of lipopolysaccharide (Barr et al 2003). Independent postmortem studies in schizophrenia provide evidence of increased syntaxin immunoreactivity in the cingulate cortex of schizophrenia brains when compared with controls (Gabriel et al 1997; Honer et al 1997). Syntaxin immunoreactivity was unchanged in schizophrenia in other brain regions including frontal, temporal, and parietal cortices (Gabriel et al 1997), as well as cerebellum (Mukaetova-Ladinska et al 2002). A study of the temporal cortex in schizophrenia patients showed higher syntaxin mRNA levels in samples of younger patients when compared with controls, and a negative correlation of mRNA levels with age in patient samples but not in controls (Sokolov et al 2000). These studies suggest a possible role for syntaxin in the pathogenesis of schizophrenia through disruption of the SNARE complex, or interference with neurotransmitter trafficking. We hypothesized that one or more polymorphisms of the syntaxin 1A gene (STX1A) would demonstrate a genetic association with schizophrenia, and examined this hypothesis across four polymorphisms in both case-control and family-based samples. Methods and Materials Patient Recruitment and Sample Collection Subjects for this study were recruited with fully informed written consent, and in accordance with University of Toronto and Medical Research Council of Canada guidelines for the ethical treatment of human subjects. Study approval for the recruitment of Portuguese subjects was given by the University of Coimbra Internal Review Board (IRB), and in the United States by the IRB of the State University of New York, Buffalo. A total of 238 nuclear families consisting of probands with schizophrenia and at least one first-degree relative were collected from both mainland Portugal (Coimbra) and the Azores islands (124 fami- lies), and from hospitals in Toronto, Ontario (114 families). In addition, 192 case-control pairs were recruited from the Toronto area. All patients had an independent clinical DSM-III-R/DSM-IV diagnosis of schizophrenia from their referring psychiatrist (American Psychiatric Association 1994). In patients from Portu- gal and the Azores, the diagnosis was confirmed with the Diagnostic Interview for Genetic Studies (Nurnberger et al 1994). A Structured Clinical Interview for Diagnosis was administered by trained research assistants to each proband from the Toronto region to confirm a DSM-III-R diagnosis of schizophrenia. In both samples, a consensus-based procedure provided the ultimate decision for the diagnostic classification of the patients. Controls were screened using the Family Interview for Genetic Studies (Maxwell 1992) and excluded if there was any personal or family history of mental illness or alcohol/substance abuse. Patients and control subjects were matched for age, gender, and self-reported From the Centre for Addiction and Mental Health (AHCW, JT, OL, TK, HHMVT, JLK), Department of Psychiatry (AHCW, HHMVT, JLK), Department of Pharmacology (AHCW, MY, HHMVT), and Institute of Medical Science (AHCW, TK, HHMVT, JLK) Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry (AM, M-HA), Univer- sity of Coimbra, Portugal; Department of Psychiatry and Behavioral Sci- ences (MTP, CNP), Upstate Medical University, State University of New York, Syracuse, New York; Research Division (MTP, CNP), Veterans Affairs Medical Center, Washington D.C.; Centre for Complex Disorders (WGH), University of British Columbia, Vancouver, British Columbia, Canada Address reprint requests to Dr. Albert H.C. Wong, Room 711, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada, M5T 1R8. Received May 6, 2003; revised February 18, 2004; accepted March 5, 2004. BIOL PSYCHIATRY 2004;56:24 –29 0006-3223/04/$30.00 doi:10.1016/j.biopsych.2004.03.008 © 2004 Society of Biological Psychiatry