The two latest additions to the burgeoning DISC1 literature provide additional support for a role of this gene in cognitive function and schizophrenia, and suggest that more comprehensive studies will be useful as we move to a greater understanding of its role in CNS function. Koike et al. (2006) found that a relatively common mouse strain has a naturally occurring mutation in DISC1 resulting in a truncated form of the protein, similar in size (exon 7 vs. exon 8 disruptions) to that observed in the members of the Scottish pedigree in which the translocation was first detected. C57/BL/6J mice, into which mutant alleles were transferred, displayed significant impairments on a spatial working memory task similar to one used in humans (Lencz et al., 2003). These data are similar to those observed by our group (Burdick et al., 2005) and others (Callicott et al., 2005; Hennah et al., 2005; Cannon et al., 2005), although no study to date has utilized the same neurocognitive tasks. Lipska et al. (2006) report that genes and proteins (NUDEL, FEZ1) known to interact with DISC1 are also aberrant in schizophrenia postmortem tissue, with some evidence that DISC1 risk polymorphisms also influence expression across the pathway.
Taken together, these two papers suggest that the assessment of genes involved in the DISC1 pathway may be worthwhile in the evaluation of working memory function. To date, most studies have focused on risk alleles within DISC1, with little attention paid to the critical interacting genes. Studies are now underway assessing the relationship between FEZ1 and NUDEL and risk for schizophrenia in a number of populations, as well as studies examining their role in neurocognitive and neuroimaging parameters. Clearly, as the Lipska paper indicates, studies that attempt to assess multiple genes in this pathway will be critical, although the common concern of power in assessing gene-gene interactions, especially across multiple genes, may be a limitation. Moreover, these studies indicate that interaction studies will need to consider additional phenotypes other than diagnosis, and perhaps “purer” tasks of neurocognitive function may be worthwhile, as suggested by Koike et al. Finally, both of these papers underscore the fact that the next wave of genetic studies of schizophrenia will encompass the use of multiple probes, whether with neurocognitive assessments, postmortem analyses, or animal models of disease, amongst others, to fully validate the relationships between putative risk genes and the pathophysiology of schizophrenia and related disorders.
Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16(12): 1399-1402. Abstract
Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8627-32. Epub 2005 Jun 6.
Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry, 2005; 62(11):1205-1213. Abstract
Hennah W, Tuulio-Henriksson A, Paunio T, Ekelund J, Varilo T, Partonen T, Cannon TD, Lonnquist J, Peltonen L. A haplotype within the DISC1 gene is associated with visual memory functions in families with high density of schizophrenia. Mol Psychiatry 2005; 10(12):1097-1103. Abstract
Lencz T, Bilder RM, Turkel E, Goldman RS, Robinson D, Kane JM, Lieberman JA. Impairments in perceptual competency and maintenance on a visual delayed match-to-sample test in first episode schizophrenia. Arch Gen Psychiatry 2003; 60(3):238-243. Abstract
View all comments by Anil MalhotraView all comments by Katherine E. Burdick
In their recent paper, Koike et al. provide new evidence in support of a genetic determinant of working memory function in the vicinity of the mouse DISC1 gene. They report their discovery of a naturally occurring DISC1 deletion variant in the 129S6/SvEv mouse strain that leads to reduced protein expression and that provides a potentially very important new tool for analyzing the cellular and behavioral phenotypes associated with DISC1 insufficiency. Given the strong evidence of a relationship between a cytogenetic abnormality that leads to DISC1 truncation in humans and major mental illness (Millar et al., 2000), this murine model stands to greatly serve our understanding of the molecular and cellular determinants of poor cognition in schizophrenia and bipolar disorder.
The authors are parsimonious in reminding us of the substantial limitations of models such as this. Specifically, the current approach does not allow for a clear statement that the DISC1 gene itself modulates the traits of interest. The DISC1 deletion variant may simply be in linkage disequilibrium with the actual phenotype-determining gene, and/or variation in DISC1 may influence cognition in a manner that is modified by a nearby genetic region. For example, Cannon et al. recently showed that a 4-SNP haplotype spanning DISC1 and an adjacent gene, translin-associated factor X (TRAX) is more predictive of anatomical and cognitive indices of reduced prefrontal cortical and hippocampal function than are any known haplotypes spanning DISC1 only. Clearly, additional consideration of the genetic environment in which DISC1 lies is necessary, and discovery of flanking regions that contain modifiers of the actions of DISC1, and vice versa, would be extremely interesting.
The greatest impact of the paper by Koike et al. is hinged on the fact that mice carrying one or two copies of the deletion variant exhibit poor choice accuracy in a delayed non-match to position task. Specifically, mutant DISC1 mice made fewer correct choices than did wild-type littermate C57 mice. Because a procedure such as this is necessarily psychologically complex, performance failure is hardly prima facie evidence for impairments of spatial working memory, or for prefrontal cortical dysfunction, in general. Nevertheless, the data are remarkable in establishing a phenotypic bridge between species and in laying the foundation for more sophisticated behavioral studies that will narrow in on the psychological constructs and neural systems affected by variation in this genetic region. Through facilitating a greater understanding of the cognitive phenotypes associated with DISC1 variation, the model should open doors to understanding key phenotypic aspects of schizophrenia and bipolar disorder.
Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice.
Proc Natl Acad Sci U S A. 2006 Feb 16; [Epub ahead of print]
Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS, Clair DM, Muir WJ, Blackwood DH, Porteous DJ. Disruption of two novel genes by a translocation co-segregating with schizophrenia.
Hum Mol Genet. 2000 May 22;9(9):1415-23.
Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory.
Arch Gen Psychiatry. 2005 Nov;62(11):1205-13.
View all comments by J David Jentsch
Disrupted In Schizophrenia 1 was first identified as a genetic susceptibility factor in schizophrenia because it is disrupted by a translocation between chromosomes 1 and 11 in a large Scottish family with a high loading of schizophrenia and related mental illness. Since then, numerous genetic studies have implicated DISC1 as a risk factor in psychiatric illness in several populations. Given the limitations on studies using brain tissue from patients, an obvious next step was to engineer knockout mice, but these have been slow in coming. As a first step toward this, Kioke and colleagues now report an unexpected naturally occurring genetic variant in the 129/SvEv mouse strain.
Kioke et al. report that the 129/SvEv mouse strain carries a 25 bp deletion in DISC1 exon 6, and that this results in a shift of open reading frame and introduction of a premature stop codon. Several embryonal stem cell lines have been isolated for the 129 strain, favoring it for gene targeting studies. However, this strain has a number of well-established behavioral characteristics (http://www.informatics.jax.org/external/festing/mouse/docs/129.shtml). Therefore, to assign any phenotype specifically to the DISC1 deletion variant, the 129 DISC1 variant had to be transferred to a C57BL/6J background, with its own, rather different but equally characteristic behavior (http://www.informatics.jax.org/external/festing/mouse/docs/C57BL.shtml). There were no detectable gross morphological alterations in the prefrontal cortex, cortex, and hippocampus on transferring the 129 DISC1 locus onto the C57BL/6J background. However, the mutation did result in working memory deficits, consistent with several reports linking DISC1 to cognition.
It is difficult to know what phenotype to expect from a mouse model for schizophrenia, but in humans it is widely believed that mutations confer only a susceptibility to developing illness. Many susceptible individuals function apparently normally, although subtle neurological endophenotypes are detectable. In individuals who do go on to develop schizophrenia, cognitive deficits are a major characteristic. These mild cognitive deficits in mice with loss of DISC1 function are therefore close to what we might predict.
The molecular mechanism by which DISC1 confers susceptibility to psychiatric illness is the subject of some debate. Sawa and colleagues have suggested that a mutant truncated protein resulting from the t(1;11) is responsible for the psychiatric disorders in the Scottish family. Millar and colleagues, however, report that there is no evidence for such a hypothetical protein in t(1;11) cell lines, but rather that the levels of DISC1 transcript and protein are reduced, consistent with a haploinsufficiency model. Identification of the deletion in mice may shed further light on this debate, since while the mutation does not affect DISC1 transcript levels, no mutant truncated protein is detectable, even though such a protein might theoretically be produced as a result of the premature stop codon. Moreover, both homozygotes and heterozygotes have cognitive impairment, demonstrating that DISC1 haploinsufficiency is sufficient to affect central nervous system function.
In this initial study, Kioke and colleagues have left many questions unanswered. In particular, the behavioral studies are limited to one working memory task and one test of locomotion. Ideally, a whole battery of behavioral and cognitive tests should be performed. Since 129/SvEv mice reportedly have impaired hippocampal function, high levels of anxiety-like behavior and altered NMDA receptor-related activity, it will be interesting to discover which, if any, of these phenotypes also co-segregate with the 129 DISC1 variant. It is also interesting to note that the 129 strain is effectively a null for full-length DISC1, but with no gross alteration in brain morphology. This has to be reconciled with the observed effect of transient RNAi mediated down-regulated expression in utero (Kamiya et al., 2005) and the possible, but still anecdotal observation of embryonic lethality in experimental DISC1 knockouts.
View all comments by Kirsty Millar