The Genetics and Biology of Disc1-An Emerging Role in Psychosis and Cognition
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.
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- "Genetic variants DISC1, PDE4B, DGKH, and RGS4, each of which affect cAMP signaling, have risk modifying effects in mood disorders and schizophrenia (Thomson et al., 2005; Talkowski et al., 2006; Baum et al., 2007; Pickard et al., 2007). None to date show clear diagnostic specificity, although there is some evidence that they are associated with impairments in cognition common to several psychiatric disorders (Porteous et al., 2006). Since cAMP activates HCN channels, variants in their genes would therefore also be good candidates for genetic risk "
ABSTRACT: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1-4) and, through activation by cyclic AMP (cAMP), represent a point of convergence for several psychosis risk genes. On the basis of positive preliminary data, we sought to test whether genetic variation in HCN1-4 conferred risk of depression or cognitive impairment in the Generation Scotland: Scottish Family Health Study. HCN1, HCN2, HCN3, and HCN4 were genotyped for 43 haplotype-tagging SNPs and tested for association with DSM-IV depression, neuroticism, and a battery of cognitive tests assessing cognitive ability, memory, verbal fluency, and psychomotor performance. No association was found between any HCN channel gene SNP and risk of depression, neuroticism, or on any cognitive measure. The current study does not support a genetic role for HCN channels in conferring risk of depression or cognitive impairment in individuals from the Scottish population.Frontiers in Genetics 07/2012; 3:116. DOI:10.3389/fgene.2012.00116
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- "One such candidate is the gene Disrupted in Schizophrenia 1 (DISC1) [Blackwood et al., 2001, 2007; Hennah et al., 2003, 2009; Hodgkinson et al., 2004; Chubb et al., 2008; Schosser et al., 2010]. DISC1 functions as a molecular scaffold protein interacting with other proteins contributing multiple neural processes involved in early corticogenesis [Millar et al., 2005; Porteous et al., 2006; Mao et al., 2009; Ming and Song, 2009]. DISC1 was first identified at the breakpoint of a balanced t(1;11) chromosomal translocation that co-segregated with schizophrenia and other affective disorders [St Clair et al., 1990; Millar et al., 2000]. "
ABSTRACT: Bipolar disorder and schizophrenia share a number of clinical features and genetic risk variants of small effect, suggesting overlapping pathogenic mechanisms. The effect of single genetic risk variants on brain function is likely to differ in people at high familial risk versus controls as these individuals have a higher overall genetic loading and are therefore closer to crossing a threshold of disease liability. Therefore, whilst the effects of genetic risk variants on brain function may be similar across individuals at risk of both disorders, they are hypothesized to differ compared to that seen in control subjects. We sought to examine the effects of the DISC1 Leu(607) Phe polymorphism on brain activation in young healthy individuals at familial risk of bipolar disorder (n = 84), in a group of controls (n = 78), and in a group at familial risk of schizophrenia (n = 47), performing a language task. We assessed whether genotype effects on brain activation differed according to risk status. There was a significant genotype × group interaction in a cluster centered on the left pre/postcentral gyrus, extending to the inferior frontal gyrus. The origin of this genotype × group effect originated from a significant effect of the presumed risk variant (Phe) on brain activation in the control group, which was absent in both high-risk groups. Differential effects of this polymorphism in controls compared to the two familial groups suggests a commonality of effect across individuals at high-risk of the disorders, which is likely to be dependant upon existing genetic background.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2012; 159B(3):343-53. DOI:10.1002/ajmg.b.32035 · 3.27 Impact Factor
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- "The existence of a clear, identifiable mutation with the high LOD scores has put DISC1 in a unique position in schizophrenia research. In addition to the familial mutation of DISC1, multiple studies of associations of different DISC1 haplotypes or SNPs with mental disorders have stimulated studying the biology of DISC1 (Porteous et al., 2006; Ross et al., 2006; Mackie et al., 2007). Numerous investigations have implicated DISC1 and interacting proteins in neuronal differentiation, migration, synaptogenesis and adult neurogenesis in the hippocampus [Kamiya et al., 2005; Duan et al., 2007; Brandon, 2007; Faulkner et al., 2008; Brandon et al., 2009]. "
ABSTRACT: Schizophrenia is a devastating neuropsychiatric disorder of unknown etiology. There is general agreement in the scientific community that schizophrenia is a disorder of neurodevelopmental origin in which both genes and environmental factors come together to produce a schizophrenia phenotype later in life. The challenging questions have been which genes and what environmental factors? Although there is evidence that different chromosome loci and several genes impart susceptibility for schizophrenia; and epidemiological studies point to broad aspects of the environment, only recently there has been an interest in studying gene × environment interactions. Recent evidence of a potential association between prenatal lead (Pb(2+)) exposure and schizophrenia precipitated the search for plausible neurobiological connections. The most promising connection is that in schizophrenia and in developmental Pb(2+) exposure there is strong evidence for hypoactivity of the N-methyl-d-aspartate (NMDA) subtype of excitatory amino acid receptors as an underlying neurobiological mechanism in both conditions. A hypofunction of the NMDA receptor (NMDAR) complex during critical periods of development may alter neurobiological processes that are essential for brain growth and wiring, synaptic plasticity and cognitive and behavioral outcomes associated with schizophrenia. We also describe on-going proof of concept gene-environment interaction studies of early life Pb(2+) exposure in mice expressing the human mutant form of the disrupted in schizophrenia 1 (DISC-1) gene, a gene that is strongly associated with schizophrenia and allied mental disorders.NeuroToxicology 12/2011; 33(3):560-74. DOI:10.1016/j.neuro.2011.11.008 · 3.05 Impact Factor