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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    ABSTRACT: Depression is a serious psychiatric condition affecting millions of patients worldwide. Unipolar depression is characterized by low mood, anhedonia, social withdrawal and other severely debilitating psychiatric symptoms. Bipolar disorder manifests in alternating depressed mood and 'hyperactive' manic/hypomanic states. Animal experimental models are an invaluable tool for research into the pathogenesis of bipolar/unipolar depression, and for the development of potential treatments. Due to their high throughput value, genetic tractability, low cost and quick reproductive cycle, zebrafish (Danio rerio) have emerged as a promising new model species for studying brain disorders. Here, we discuss the developing utility of zebrafish for studying depression disorders, and outline future areas of research in this field. We argue that zebrafish represent a useful model organism for studying depression and its behavioral, genetic and physiological mechanisms, as well as for anti-depressant drug discovery.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2014; 55. DOI:10.1016/j.pnpbp.2014.03.003 · 4.03 Impact Factor
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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.
    Journal of chemical neuroanatomy 08/2013; 53. DOI:10.1016/j.jchemneu.2013.07.002 · 2.52 Impact Factor
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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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    ABSTRACT: Growing evidence for genetic overlap between schizophrenia (SCZ) and bipolar disorder (BPD) suggests that causal variants of large effect on disease risk may cross traditional diagnostic boundaries. Extended multigenerational families with both SCZ and BPD cases can be a valuable resource for discovery of shared biological pathways because they can reveal the natural evolution of the underlying genetic disruptions and their phenotypic expression. We investigated a deletion at the SLC1A1 glutamate transporter gene originally identified as a copy number variant exclusively carried by members of a 5-generation Palauan family. Using an expanded sample of 21 family members, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three "obligate-carrier" parents and one unaffected sibling, while four marry-in parents were non-carriers. Linkage analysis under an autosomal dominant model generated a LOD-score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the transcription start site, and the first 59 amino acids of the protein, including the first transmembrane Na(2+) /dicarboxylate symporter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2013; 162(2). DOI:10.1002/ajmg.b.32125 · 3.27 Impact Factor
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