RESEARCH ARTICLE Evidence for an Interaction of Schizophrenia Susceptibility Loci on Chromosome 6q23.3 and 10q24.33–q26.13 in Arab Israeli Families A. Alkelai, 1 Y. Kohn, 1 T. Olender, 2 K. Sarner-Kanyas, 1 A. Rigbi, 1 A. Hamdan, 3 E. Ben-Asher, 2 D. Lancet, 2 and B. Lerer 1 * 1 Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah—Hebrew University Medical Center, Jerusalem, Israel 2 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel 3 Regional Mental Health Center, Taibe, Israel Received 17 April 2008; Accepted 25 November 2008 A genome scan for schizophrenia related loci in Arab Israeli families by Lerer et al. [Lerer et al. (2003); Mol Psychiatry 8:488–498] detected significant evidence for linkage at chromo- some 6q23. Subsequent fine mapping [Levi et al. (2005); Eur J Hum Genet 13:763–771], association [Amann-Zalcenstein et al. (2006); Eur J Hum Genet 14:1111–1119] and replication studies [Ingason et al. (2007); Eur J Hum Genet 15:988–991] identified AHI1 as a putative susceptibility gene. The same genome scan revealed suggestive evidence for a schizophrenia susceptibility locus in the 10q23–26 region. Genes at these two loci may act independently in the pathogenesis of the disease in our homo- geneous sample of Arab Israeli families or may interact with each other and with other factors in a common biological pathway. The purpose of our current study was to test the hypothesis of genetic interaction between these two loci and to identify the type of interaction between them. The initial stage of our study focused on the 10q23–q26 region which has not been explored further in our sample. The second stage of the study included a test for possible genetic interaction between the 6q23.3 locus and the refined 10q24.33–q26.13 locus. A final candidate region of 19.9 Mb between markers D10S222 (105.3 Mb) and D10S587 (125.2 Mb) was found on chromosome 10 by non-parametric and parametric linkage analyses. These linkage findings are consistent with previous reports in the same chromosomal region. Two-locus multipoint linkage analysis under three com- plex disease inheritance models (heterogeneity, multiplicative, and additive models) yielded a best maximum LOD score of 7.45 under the multiplicative model suggesting overlapping function of the 6q23.3 and 10q24.33–q26.13 loci. Ó 2009 Wiley-Liss, Inc. Key words: schizophrenia; chromosome 10q; chromosome 6q; two locus linkage; epistasis INTRODUCTION Schizophrenia (OMIM #181500) is a severe, chronic neuropsy- chiatric disorder with a lifetime prevalence of 1%. An unknown number of genes are thought to be involved in pathogenesis of schizophrenia interacting with each other, with epigenetic pro- cesses and with environmental factors [Waterwort et al., 2002; Ross et al., 2006]. Linkage and association studies have led to identifica- tion of several chromosomal regions that are thought to harbor genes conferring risk for schizophrenia [Waterwort et al., 2002; Harrison and Owen, 2003; Shirts and Nimgaonkar, 2004; Ross et al., 2006; Straub and Weinberger, 2006]. Several putative susceptibility genes have been identified in these linked regions or by a candidate gene approach, including NRG1, DTNBP1, RGS4, COMT, PRODH, DISC1, GRM3, DAOA(G72/G30), PP3CC, CHRNA7, AKT1, GAD1, ERBB4, FEZ1, MUTED, MRDS1, NPAS3, and GRIK4 [Waterwort et al., 2002; Harrison and Owen, 2003; Shirts and Nimgaonkar, 2004; Ross et al., 2006; Straub and Weinberger, 2006]. These genes could act independently or could interact to cause schizophrenia. Additional supporting information may be found in the online version of this article. *Correspondence to: B. Lerer, Department of Psychiatry, Hadassah—Hebrew University Medical Center, Ein Karem, Jerusalem 91120, Israel. E-mail: lerer@cc.huji.ac.il Published online 16 January 2009 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.b.30918 How to Cite this Article: Alkelai A, Kohn Y, Olender T, Sarner-Kanyas K, Rigbi A, Hamdan A, Ben-Asher E, Lancet D, Lerer B. 2009. Evidence for an Interaction of Schizophrenia Susceptibility Loci on Chromosome 6q23.3 and 10q24.33–q26.13 in Arab Israeli Families. Am J Med Genet Part B 150B:914–925. Ó 2009 Wiley-Liss, Inc. 914 Neuropsychiatric Genetics