Recent advances in genetic studies in psychiatry have identified many candidate factors that may alter susceptibility to schizophrenia. Biological studies have begun to clarify that some of them may contribute to common disease pathways in brain development.

DISC1 is one of the major genetic susceptibility candidates for schizophrenia. It is a multifunctional protein that interacts with other molecules related to neurodevelopment. Ikeda and colleagues (Ikeda et al., 2008) conducted a genetic association study for several DISC1 interacting factors, including NDEL1, LIS1, 14-3-3 epsilon (YWHAE), Grb2, and KIF5A. They reported the association of six SNPs of YWHAE with schizophrenia, but no association of SNPs in other molecules in their sample sets. Given that one of the six SNPs is located in the 5’ flanking region of YWHAE, the authors hypothesize that it may have functional effects. They obtained evidence for a correlation between this SNP and expression levels of YWHAE in lymphocytes of health control subjects. Ikeda and colleagues also found disturbances of working memory and anxiety-related behavior in YWHAE heterozygous knockout mice. They have previously reported defects of neuronal migration in cerebral cortex and hippocampus of these mice (Toyo-oka et al., 2003), supporting the notion that YWHAE may be a susceptibility gene for schizophrenia.

Although additional genetic studies in different populations are required to confirm YWHAE as a candidate gene for schizophrenia, the biology-based genetic approach employed in this study is very productive. In fact, recent association studies have reported that NDEL1 and NDE1, two major DISC1 binding partners, are associated with schizophrenia (Hennah et al., 2007; Burdick et al., 2008). Our group has also recently identified an interaction between DISC1 and PCM1, another susceptibility factor for schizophrenia (Gurling et al., 2006), and characterized the functional role of their interaction (Kamiya et al., in press). Additional risk factors for schizophrenia, as well as their disease-causing mutations, will possibly be found in DISC1-mediated disease pathways. Furthermore, cross-breeding among animal models of these factors will provide us important clues for further analysis of their molecular mechanisms in DISC1 pathways, especially in the context of neuronal development. In particular, the questions should be addressed of how these pathways impact on disease-associated disturbances of neuronal circuit formation during brain development and resultant behavioral alterations that occur only after puberty.

References:

Burdick KE, Kamiya A, Hodgkinson CA, Lencz T, DeRosse P, Ishizuka K, Elashvili S, Arai H, Goldman D, Sawa A, Malhotra AK. Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: evidence of epistasis and competitive binding. Hum Mol Genet. 2008 Aug 15;17(16):2462-73. Abstract

Gurling HM, Critchley H, Datta SR, McQuillin A, Blaveri E, Thirumalai S, Pimm J, Krasucki R, Kalsi G, Quested D, Lawrence J, Bass N, Choudhury K, Puri V, O'Daly O, Curtis D, Blackwood D, Muir W, Malhotra AK, Buchanan RW, Good CD, Frackowiak RS, Dolan RJ. Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia. Arch Gen Psychiatry. 2006 Aug 1;63(8):844-54. Abstract

Hennah W, Tomppo L, Hiekkalinna T, Palo OM, Kilpinen H, Ekelund J, Tuulio-Henriksson A, Silander K, Partonen T, Paunio T, Terwilliger JD, Lönnqvist J, Peltonen L. Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1. Hum Mol Genet. 2007 Mar 1;16(5):453-62. Abstract

Ikeda M, Hikita T, Taya S, Uraguchi-Asaki J, Toyo-Oka K, Wynshaw-Boris A, Ujike H, Inada T, Takao K, Miyakawa T, Ozaki N, Kaibuchi K, Iwata N. Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. Hum Mol Genet. 2008 Jul 24; Abstract

Toyo-oka K, Shionoya A, Gambello MJ, Cardoso C, Leventer R, Ward HL, Ayala R, Tsai LH, Dobyns W, Ledbetter D, Hirotsune S, Wynshaw-Boris A. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet. 2003 Jul 1;34(3):274-85. Abstract

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