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: 10.93). 12/2004; 75(5):862-72. DOI: 10.1086/425586
Source: PubMed


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
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    • "Disrupted-in-Schizophrenia 1 (DISC1) and DISC2 genes are located at the breakpoint of a chromosomal translocation at 1q42.1 (1;11) (q42.1;q14.3), which was firstly described to be linked to major psychiatric disorders, including schizophrenia, in a Scottish family.1 Subsequent studies on different ethnic populations provided further evidence supporting the role of DISC1 as a susceptibility gene for Schizophrenia spectrum disorders.2,3,4,5,6,7,8,9,10,11,12 "
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    ABSTRACT: Objective DISC1 gene is one of the main candidate genes for schizophrenia since it has been associated to the illness in several populations. Moreover, variations in several DISC1 polymorphisms, and in particular Ser704Cys SNP, have been associated in schizophrenic patients to structural and functional modifications in two brain areas (pre-frontal cortex and hippocampus) that play a central role in the genesis of psychotic symptoms. This study tested the association between Ser704Cys DISC1 polymorphism and the clinical onset of psychosis. Methods Two hundred and thirteen Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys) SNP of the DISC1 gene. The clinical severity of the illness was assessed using SAPS and SANS scales. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects. Results Patients homozygous for the Ser allele of the Ser704Cys DISC1 SNP had significantly (p<0.05) higher rates at the positive symptoms dimension (SAPS-SANS scales) and hallucinations item, compared to Cys carriers. Conclusion DISC1 gene variations may modulate the clinical severity of the psychosis at the onset of the disorder.
    Full-text · Article · Apr 2014 · Psychiatry investigation
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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.
    Full-text · Article · Mar 2014 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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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.
    Full-text · Article · Aug 2013 · Journal of chemical neuroanatomy
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