Article

The genetics and biology of DISC1--an emerging role in psychosis and cognition.

Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Crewe Road South, Edinburgh.
Biological Psychiatry (Impact Factor: 9.25). 08/2006; 60(2):123-31. DOI: 10.1016/j.biopsych.2006.04.008
Source: PubMed

ABSTRACT In the developing field of biological psychiatry, DISC1 stands out by virtue of there being credible evidence, both genetic and biological, for a role in determining susceptibility to schizophrenia and related disorders. We highlight the methodologic paradigm that led to identification of DISC1 and review the supporting genetic and biological evidence. The original finding of DISC1 as a gene disrupted by a balanced translocation on chromosome 1q42 that segregates with schizophrenia, bipolar disorder, and recurrent major depression has sparked a number of confirmatory linkage and association studies. These indicate that DISC1 is a generalizable genetic risk factor for psychiatric illness that also influences cognition in healthy subjects. DISC1 has also been shown to interact with a number of proteins with neurobiological pedigrees, including Ndel1 (NUDEL), a key regulator of neuronal migration with endo-oligopeptidase activity, and PDE4B, a phosphodiesterase that is critical for cyclic adenosine monophosphate signaling and that is directly linked to learning, memory, and mood. Both are potential "drug" targets. DISC1 has thus emerged as a key molecular player in the etiology of major mental illness and in normal brain processes.

0 Bookmarks
 · 
70 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD). Here we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples. Although no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling. The findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16.
    BMC Medical Genetics 01/2014; 15(1):2. · 2.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nuclear distribution factor E homolog like 1 (NDEL1) plays an important role in mitosis, neuronal migration, and microtubule organization during brain development by binding to disrupted-in-schizophrenia-1 (DISC1) or lissencephaly (LIS1). Although some evidence has suggested that DISC1 expression is altered in epilepsy, few studies have reported the relationship between NDEL1 and the etiology of epilepsy. In present study, we first investigated the expression of NDEL1 and its binding protein DISC1 after pilocarpine-induced epilepsy in male C57BL/6 mice. Data revealed that the mRNA and protein expression of NDEL1 and DISC1 in the whole hippocampus increased during the spontaneous seizure period after status epilepticus (SE). Interestingly, however, the expression of NDEL1 was decreased in the cornu ammonis 3 (CA3) and dentate gyrus (DG) regions. Moreover, SE also increased the number of blood vessels that fed the CA3 and DG regions of the hippocampus and increased the incidence of abnormalities in capillary network formation where NDEL1 protein was expressed positively. Meanwhile, the expression of phosphorylated ERK (p-ERK) was also increased during the spontaneous seizure period, with a similar expression pattern as NDEL1 and DISC1. Based on these results, we hypothesize that NDEL1 might interact with DISC1 to activate ERK signaling and function as a potential protective factor during the spontaneous seizure period after pilocarpine-induced SE.
    Neuroscience 03/2014; · 3.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite intensive research over many years, the treatment of schizophrenia remains a major health issue. Current and emerging treatments for schizophrenia are based upon the classical dopamine and glutamate hypotheses of disease. Existing first and second generation antipsychotic drugs based upon the dopamine hypothesis are limited by their inability to treat all symptom domains and their undesirable side effect profiles. Third generation drugs based upon the glutamate hypothesis of disease are currently under evaluation but are more likely to be used as add on treatments. Hence there is a large unmet clinical need. A major challenge in neuropsychiatric disease research is the relative limited knowledge of disease mechanisms. However, as our understanding of the genetic causes of the disease evolves, novel strategies for the development of improved therapeutic agents will become apparent. In this review we consider the current status of knowledge of the genetic basis of schizophrenia, including methods for identifying genetic variants associated with the disorder and how they impact on gene function. Although the genetic architecture of schizophrenia is complex, some targets amenable to pharmacological intervention can be discerned. We conclude that many challenges lie ahead but the stratification of patients according to biobehavioural constructs that cross existing disease classifications but with common genetic and neurobiological bases, offer opportunities for new approaches to effective drug discovery.
    Pharmacology [?] Therapeutics 01/2014; · 7.79 Impact Factor