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Disrupted in Schizophrenia 1 (DISC1): Association with Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder

Section of Human Neurogenetics and Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 12/2004; 75(5):862-72. DOI: 10.1086/425586
Source: PubMed

ABSTRACT Schizophrenia, schizoaffective disorder, and bipolar disorder are common psychiatric disorders with high heritabilities and variable phenotypes. The Disrupted in Schizophrenia 1 (DISC1) gene, on chromosome 1q42, was originally discovered and linked to schizophrenia in a Scottish kindred carrying a balanced translocation that disrupts DISC1 and DISC2. More recently, DISC1 was linked to schizophrenia, broadly defined, in the general Finnish population, through the undertransmission to affected women of a common haplotype from the region of intron 1/exon 2. We present data from a case-control study of a North American white population, confirming the underrepresentation of a common haplotype of the intron 1/exon 2 region in individuals with schizoaffective disorder. Multiple haplotypes contained within four haplotype blocks extending between exon 1 and exon 9 are associated with schizophrenia, schizoaffective disorder, and bipolar disorder. We also find overrepresentation of the exon 9 missense allele Phe607 in schizoaffective disorder. These data support the idea that these apparently distinct disorders have at least a partially convergent etiology and that variation at the DISC1 locus predisposes individuals to a variety of psychiatric disorders.

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Available from: Colin A Hodgkinson, Jul 28, 2015
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    • "Likewise, the DISC1 gene is conserved among rats, mice and zebrafish, and is one of several key genes strongly linked to both schizophrenia and BD (Hodgkinson et al. 2004). In particular, Disc1 morpholino knockdown in zebrafish resulted in abnormal cell migration and low neural population in the cranial neural crest (Morris 2009). "
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    • "DBZ (DISC1-binding zinc finger protein) (also known as Su48 and KIAA0844) was identified as a binding partner of DISC1 by yeast-2-hybrid screening of a human brain cDNA library. DISC1 is a key genetic risk factor for major mental disorders such as schizophrenia, mood disorders, autism and Asperger syndrome, and plays a role in multiple cellular processes during and after brain development (Callicott et al., 2005; Hennah et al., 2003; Hodgkinson et al., 2004; Kilpinen et al., 2008; Song et al., 2008). On the other hand, the results of several genetic analyses have suggested an association between DBZ gene and mental illness (Liu et al., 2003; Marcheco-Teruel et al., 2006; Moens et al., 2011; Segurado et al., 2003). "
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    ABSTRACT: Disrupted-in-schizophrenia 1 (DISC1)-binding zinc finger protein (DBZ) is a DISC1-interacting molecule and the interaction between DBZ and DISC1 is involved in neurite outgrowth in vitro. DBZ is highly expressed in brain, especially in the cortex. However, the physiological roles of DBZ in vivo have not been clarified. Here, we show that development of basket cells, a morphologically defined class of parvalbumin (PV)-containing interneurons, is disturbed in DBZ knockout (KO) mice. DBZ mRNA was highly expressed in the ventral area of the subventricular zone of the medial ganglionic eminence, where PV-containing cortical interneurons were generated, at embryonic 14.5 days (E14.5). Although the expression level for PV and the number of PV-containing interneurons were not altered in the cortices of DBZ KO mice, basket cells were less branched and had shorter processes in the somatosensory cortices of DBZ KO mice compared with those in the cortices of WT mice. Furthermore, in the somatosensory cortices of DBZ KO mice, the level of mRNAs for the gamma-aminobutyric acid-synthesizing enzymes GAD67 was decreased. These findings show that DBZ is involved in the morphogenesis of basket cells.
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    • "A series of studies over several decades showed that a chromosomal translocation disrupting the DISC1 gene co-segregated with 18 cases of ''major mental illness'' covering a broad range of psychiatric disorders including SCZ, BPD, and major depression [St Clair et al., 1990; Blackwood et al., 2001]. Subsequent research has shown that DISC1 disruptions are associated with both SCZ and BPD [e.g., Hodgkinson et al., 2004; Hamshere et al., 2005; Hennah et al., 2009] and can influence a broad range of neurodevelopmental and synaptogenic pathways [Chubb et al., 2008; Hennah and Porteous, 2009]. Extended multigenerational pedigrees with major mental illness, such as the Scottish DISC1 family, provide a valuable resource for gene discovery because they reveal the natural evolution of genetically transmitted mutations and their broad spectrum of phenotypic expression. "
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