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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    ABSTRACT: Cell positioning and neuronal network formation are crucial for proper brain function. Disrupted-in-Schizophrenia 1 (DISC1) is anterogradely transported to the neurite tips, together with Lis1, and functions in neurite extension via suppression of GSK3β activity. Then, transported Lis1 is retrogradely transported and functions in cell migration. Here, we show that DISC1-binding zinc finger protein (DBZ), together with DISC1, regulates mouse cortical cell positioning and neurite development in vivo. DBZ hindered Ndel1 phosphorylation at threonine 219 and serine 251. DBZ depletion or expression of a double-phosphorylated mimetic form of Ndel1 impaired the transport of Lis1 and DISC1 to the neurite tips and hampered microtubule elongation. Moreover, application of DISC1 or a GSK3β inhibitor rescued the impairments caused by DBZ insufficiency or double-phosphorylated Ndel1 expression. We concluded that DBZ controls cell positioning and neurite development by interfering with Ndel1 from disproportionate phosphorylation, which is critical for appropriate anterograde transport of the DISC1-complex. Copyright © 2015 the authors 0270-6474/15/352942-17$15.00/0.
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    ABSTRACT: Structural brain abnormalities have been extensively investigated as potential endophenotypes of schizophrenia. Apart from enlarged ventricles and whole brain volume reductions, no other consistently replicated brain morphometric abnormalities have emerged from these studies. The differential effect of genetic variants on brain morphometry could be a major source of variability underlying such inconsistent findings. Schizophrenia is a polygenic disorder, wherein the complex interplay between common risk variants of small effect, rare risk alleles of large effect as well as epigenetic interactions confer vulnerability and mediate the final expression of the clinical phenotype. A comprehensive understanding of the effect of risk genes on brain morphometry is essential for linking the structural endophenotype/s that can be linked with the genetic diathesis for development of schizophrenia. We systematically reviewed published literature to examine the effect of genes mediating neurodevelopment and brain signalling on brain morphometry. A majority of polymorphisms of the above genes was shown to be associated with whole brain and regional volumetric reductions; but importantly, many genes showed mixed effects, i.e., both volume reductions and increases. Modelling such complex interactions of the large number of risk genes on brain volume in vivo poses considerable practical challenges in having adequate sample sizes as well as imaging data for reliable quantification. Therefore, it is recommended that the field should move beyond association studies of the morphometric effect of single or limited number of gene polymorphisms in clinical populations to modelling the complex epistatic and epigenetic interactions in silico or using animal and cellular models.
    Neurology Psychiatry and Brain Research 03/2015; 21(1). DOI:10.1016/j.npbr.2014.11.003 · 0.10 Impact Factor
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    ABSTRACT: Even though the role of the DICS1 gene as a risk factor for schizophrenia is still unclear, there is substantial evidence from functional and cell biology studies that supports the connection of the gene with schizophrenia. The studies associating the DISC1 gene with schizophrenia in Asian populations are limited to East-Asian populations. Our study examined several DISC1 markers of schizophrenia that were identified in the Caucasian and East-Asian populations in Malaysia and assessed the role of rs2509382, which is located at 11q14.3, the mutual translocation region of the famous DISC1 translocation [t (1; 11) (p42.1; q14.3)]. We genotyped eleven single-neucleotide polymorphism (SNPs) within or related to DISC1 (rs821597, rs821616, rs4658971, rs1538979, rs843979, rs2812385, rs1407599, rs4658890, and rs2509382) using the PCR-RFLP methods. In all, there were 575 participants (225 schizophrenic patients and 350 healthy controls) of either Malay or Chinese ethnicity. The case-control analyses found two SNPs that were associated with schizophrenia [rs4658971 (p=0.030; OR=1.43 (1.35-1.99) and rs1538979-(p=0.036; OR=1.35 (1.02-1.80)] and rs2509382-susceptibility among the males schizophrenics [p=0.0082; OR=2.16 (1.22-3.81)]. This is similar to the meta-analysis findings for the Caucasian populations. The study supports the notion that the DISC1 gene is a marker of schizophrenia susceptibility and that rs2509382 in the mutual DISC1 translocation region is a susceptibility marker for schizophrenia among males in Malaysia. However, the finding of the study is limited due to possible genetic stratification and the small sample size.
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