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.
- SourceAvailable from: Georgina Hosang
[Show abstract] [Hide abstract]
- "Other SNPs showing suggestive association included SNPs within known candidate genes for BD, such as PDE4B (p = 7.45×10-5). PDE4B encodes a phosphodiesterase that binds directly with DISC1, and is critical for cyclic adenosine monophosphate signalling, which is linked to learning, memory, and mood , and shows association with SCZ [41-44], and to some degree with BD . SNPs were identified with suggestive association at a number of other genes with plausible biological arguments for involvement in, and/or previous associations to BD, such as NRG3 (p = 5.53×10-6), GAD2 (p = 2.21×10-5), GRIK2 (p = 4.18×10-5), GABRG3 (p = 3.83×10-5), and the synapse-associated protein 102 gene, DLG3 (p = 5.31×10-5). "
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. DOI:10.1186/1471-2350-15-2 · 2.08 Impact Factor
[Show abstract] [Hide abstract]
- "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
[Show abstract] [Hide abstract]
- "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 · 3.42 Impact Factor