Disrupted-in-Schizophrenia-1 Walter J. Muir, MBChB, FRCPsych, Benjamin S. Pickard, PhD, and Douglas H.R. Blackwood, MBChB, PhD, FRCPE, FRCPsych, FRSE

Corresponding author Walter J. Muir, MBChB, FRCPsych Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Morningside Park, Edinburgh, Scotland EH10 5HF, United Kingdom. E-mail: [email protected] Current Psychiatry Reports 2008, 10:140–147 Current Medicine Group LLC ISSN 1523-3812 Copyright © 2008 by Current Medicine Group LLC

Chromosomal abnormalities can be powerful tools to identify genes that influence disease risk. The study of a chromosome translocation that segregated with severe psychiatric illness in a large family led directly to the discovery of a gene disrupted by a chromosomal breakpoint. Disrupted-in-Schizophrenia-1 (DISC1) is now an important candidate risk gene for schizophrenia and affective disorders. We review the work that led up to this discovery and the evidence that it is important in the wider population with schizophrenia and affective disorders. We also discuss the latest findings on the neuronal functions of the protein DISC1 encoded by the gene.

Introduction For the people who have it, for the families who support them, for the psychiatrists who seek to treat it, and for society as a whole, the disorder we term schizophrenia has a manifest importance. Yet it presently can only be defined by the reporting and observation of a series of changes in cognitions and behaviors; there are still no additional markers or investigations that independently confirm our clinical decision. Kraepelin’s division of psychosis into schizophrenic and manic depressive types is still highly useful at the individual level. Along with our clinical experience and studies of the natural history of these disorders, it helps us to decide which type of treatment to use and to make a reasonable estimate of prognosis. However, we believe the application of the dichotomy has gone beyond Kraepelin’s original intentions, thus hampering our understanding of psychotic illness. A widespread assumption was (and still is) that the dichotomy defined not only two separate illnesses but that each illness was a homogeneous entity within itself. Thus, it was reasonable to group

together all people with a diagnosis of schizophrenia into a given study and to make valid interpretations from this that applied to all people with schizophrenia. Similarly, it was formerly common to study people with major depressive disorder (MDD) together with people with bipolar affective disorder (BAD), as both were then grouped nosologically as having manic depressive illness. There are phenomenologic and therapeutic similarities between depressive episodes seen in MDD and those seen in BAD, but we would no longer consider their underlying etiology to be identical. A point emerging from recent genetic studies of schizophrenia and other psychoses is that they are probably not etiologically unitary. There may be a “group of schizophrenias,” a “group of bipolar illnesses,” and situations in which proximate causes, such as genetic risk factors, have the potential to lead to both outcomes in a given individual. Secondary factors—other genes, environmental influences, and social factors—then determine the final clinical expression.

Search for the genetic basis of schizophrenia Although we now believe schizophrenia has an underlying biological basis, it is one whose presentation, course, and outcome are modulated by social and external environmental factors. To understand this interplay, we need to tease out the various component factors involved, but the biological underpinnings have not been easy to delineate. Abnormal brain neurochemistry was originally postulated on knowledge of the pharmacology of treatments effective in controlling positive symptoms, or of drugs, such as amphetamines, whose long-term use precipitated a paranoid illness near identical to schizophrenia. The dopamine and glutamate systems presently are the best candidates. Imaging and anatomic studies have revealed large-scale (eg, ventricular enlargement) and fine-scale (neuronal circuitry microarchitecture) changes, with the limbic system and frontal cortex consistently emerging as the regions most involved. However, there are still inconsistencies among different studies, failures of replication, and concerns about lack of specificity of findings to schizophrenia. Whereas some of these difficulties may be genuine problems relating to study design and quality, many also could be explained as an outcome of assumed homogeneity.

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However, the clearest factors that alter the risk of developing schizophrenia are genetic. We cannot escape our genes’ influence. Their importance usually is a matter of degree, especially for “complex” disorders such as schizophrenia. The classical approach to determining whether an illness is heritable and whether this heritability has a genetic basis follows three routes. First, heritability is tested by seeing whether the illness runs in families. Some important genetic disorders (eg, Down syndrome) usually do not. However, the risk of developing schizophrenia in near relatives of an individual with the illness is markedly raised over that of the general population and well defined. To decide whether these familial risks are substantially genetic, we turn to twins to see if schizophrenia occurs more often in both twins of identical rather than nonidentical pairs. For schizophrenia, the concordance rate is much higher for identical twins, indicating that a large contribution (not all) to heritability is genetic. The remainder is due to environmental causes or to differences that exist between the identical twins’ genomes, such as level of DNA methylation. We do not discuss such epigenetic effects in this review, but they likely will be important areas of future research. Adoption studies form the final approach. If adoption occurs very early in life, then the effects of upbringing/parenting and differential environment can be examined. Adoptees (with biological parent[s] with schizophrenia) placed in a home in which neither adoptive parent has schizophrenia are compared with adoptees (with healthy biological parents) who by chance were brought up by an adoptive parent who developed schizophrenia. Overall, the risk of developing schizophrenia remains at the rate of biological relatedness. If environment is an important influence, then the influence must be exerted early on (ie, before adoption). These approaches confirm that schizophrenia has a genetic basis and is heritable. The last two decades have seen the field move on to try to identify the specific genetic risk factors involved. Several candidate genes recently have emerged. New molecular biology tools developed in the 1970s and 1980s helped to start this search. Basically, they detect specific local differences in DNA sequence (polymorphisms) between individuals and use them to track and map regions of chromosomes associated with disease in families. In a nutshell, this is the basis of linkage analysis, which statistically tests the likelihood of cosegregation between a marker and an illness locus. If DNA and clinical information can be obtained from a group of large families affected multiple times with illness, then there may be sufficient power to identify the chromosomal position of a susceptibility gene. By the early 1980s, several research groups were actively recruiting large families affected multiple times with schizophrenia to participate in such studies.

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Early Linkage Studies The first large-scale linkage study on schizophrenia itself followed a report of a chromosome abnormality, a partial trisomy (as an unbalanced outcome of a familial translocation between chromosomes 1 and 5), in an uncle and nephew, both of whom had schizophrenia [1]. Using this clue and choosing markers mapping to the chromosome 5 trisomy, Sherrington et al. [2] reported linkage to schizophrenia in a set of Icelandic and English families. This was groundbreaking and served to massively increase the interest in our field. However, a problem almost immediately emerged: seeming lack of replication. Many groups (eg, St Clair et al. [3]) found that in their particular families, these markers on chromosome 5 did not segregate with the illness. It was suggested that not only was the Sherrington et al. [2] study in error (no evidence exists to support this) but that the whole linkage method was not applicable to complex “polygenic” conditions such as schizophrenia. Not considered was the possibility of locus heterogeneity—that the studies were correct and implied a risk locus on chromosome 5 in some families, but that in others, the same clinical illness could emerge from a different set of genetic factors. Criticisms were also raised that some of the family sets contained individuals with BAD and schizophrenia. Although different models of caseness were used in the analyses, the inference was that assortative mating occurred in these families or that for other reasons, BAD cases were phenocopies (oddly enough, the presence of MDD in the families did not arouse such comment). The historical Kraepelinian dichotomy was being used in another way: schizophrenia must breed true to form. Part of the difficulty was that any degree of etiologic/ locus heterogeneity would decrease the standard linkage approach’s power substantially. It might be hard to find schizophrenia susceptibility genes. One solution is to look at large extended families affected multiple times by illness. These should be more etiologically homogenous than a collection of independent families, and their intrinsic power to detect linkage could be modeled to see if they could generate a statistically significant result. We later used this approach to screen a very large extended family with probes spaced across the whole set of chromosomes and revealed a genetic risk locus for BAD on chromosome 4p [4]. However, the genome has more than 25,000 genes, many of which are brain expressed. Linkage analysis defines a susceptibility region but cannot identify the gene and its mutation responsible for the effect. Even with the advent of the complete Human Genome Project (annotating the positions and sequence of all human genes) and the HapMap Project (cataloguing common polymorphisms in the population), linkage analysis is only starting to be successful in psychiatric illness, notably the genes for neuregulin and dysbindin. In most cases, it is easier if we have pointers to where to look.

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Cytogenetic Approaches In other inherited diseases (eg, Duchenne muscular dystrophy), large-scale cytogenetic abnormalities (chromosomal breaks in people with illness) provided direct positional pointers to a disease locus. For schizophrenia, we were fortunate to have access to a unique Scottish resource. The 1960s and 1970s were the heyday of classical chromosome analysis, and the UK Medical Research Council was at the forefront. The human chromosome count was correctly determined in 1956; rapidly thereafter, many large-scale abnormalities were identified. For example, a single issue of the Lancet in 1959 reported chromosome abnormalities in Down syndrome, Turner’s syndrome, and Klinefelter’s mosaicism. Better stains later helped to correctly identify individual chromosomes and alterations of structure within them. The ability to detect these prompted large-scale population surveys that included individuals with mental retardation (the UK term currently is learning disability [not the same meaning as in the DSM-IV]) or mental illness. However, this approach generated its own problems. Based on surveys of maximum-security psychiatric hospitals, the XYY karyotype was claimed to be associated with antisocial behavior [5,6], a conjecture rejected after wider incidence studies were conducted in the nonpsychiatric population. However, this did spur other surveys, and the data collected went further than simply itemizing chromosomal abnormalities. Scotland’s genealogical records allow pedigrees to be traced over many generations, and cooperation of families with inherited chromosome anomalies was striking. All available and consenting members of a family were karyotyped and, importantly, their clinical progress followed up annually through contact with their general practitioners. In this way, illness onset and type could be compared between carriers and noncarriers. One inherited rearrangement involves part of one chromosome exchanging places with another part of a different chromosome. This can occur within a chromosomal arm (interstitial rearrangement). However, it occurs more often between parts of an entire chromosomal arm. In a germ cell with such reordered chromosomes, there may be no overall loss or gain of chromosomal material (a balanced reciprocal translocation). Many of these do not directly affect the carrier but come to light through miscarriages, for when they are combined with unrearranged chromosomes from their partner, the combination can result in an unbalanced zygotic karyotype (a partial deletion or duplication) and lead to such large-scale gene copy number alterations that the fetus does not survive to term.

Chromosome anomalies and psychiatric illness Clinical reports suggested a higher-than-expected notification rate of psychiatric illness, including schizophrenia in the family of a person with one such balanced reciprocal translocation. The abnormality was originally detected in

an early large study. The family was extensively surveyed to trace the inheritance of the anomaly [7]. The balanced rearrangement involves a stretch of the long arm of chromosome 1 being “swapped” with a stretch of the long arm of chromosome 11, stated in cytogenetic nomenclature as t(1;11)(q42.2;q14.1). Here, “t” indicates a translocation, the first parentheses contain the two chromosomes involved, and the second parentheses the breakpoints as defined by the banding pattern nomenclature for the long (q) or short (p) arm of the respective chromosomes. A straightforward hypothesis indicates that carrying the chromosome abnormality increases the risk for developing a psychiatric illness. We interviewed as many family members as possible using a well-validated structured psychiatric rating schedule (Schedule for Affective Disorders and Schizophrenia-Lifetime Version). The psychiatrists were blind to karyotype status, and there was no evidence of mental retardation or dysmorphic features. For most intents and purposes, they were the same as anyone else in the general population, but we found that a considerable number had experienced severe MDD, and others had schizophrenia. However, as might be expected, others in the family had minor depression, anxiety disorders, and other similar, less severe psychiatric diagnoses. An obvious statistical question was this: given the family structure, is there a significant cosegregation of the translocation with mental illness? The basic principles of linkage apply, and the significance was high for severe psychiatric illness, including schizophrenia and MDD [8]. All the people in this family who had severe psychiatric illness carried the translocation. Most of those with more minor illness had no translocation. Translocation carriers who had no psychiatric illness, even though they had passed the age of maximum risk for onset, were also found. Thus, the risk generation could not be absolute, and other factors clearly can counteract any increased risk from translocation carriage. In a follow-up study on the family 10 years later, additional members who had developed severe mental illness, including BAD, were found. The logarithm of the odds (LOD) score statistic had increased to more than 7 (usually interpreted as P < 10 -7 that the association occurs by chance) when MDD, schizophrenia, and BAD were considered as cases. Adding in minor illnesses decreased the LOD score dramatically [9]. A computer averaging technique was also used to analyze a simple scalp-recorded electroencephalogram. Interspersed within a background of repeated tones played through headphones were a series of unpredictable tones of different pitch. Asking the person to attend to the latter and analyzing the responses to the unpredictable and predictable separately produces a (positive-going) waveform of approximately 300 ms (thus termed P300) after the tone—something not seen when the responses to routine sounds are averaged. This marker has been widely studied in psychiatric illness, especially schizophrenia, in which its amplitude is

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decreased and onset timing delayed—features that are reasonably robust to medication and age effects and reliable on test-retest estimation. The results in the family were most clear for amplitude: those with the translocation, including those with no psychiatric illness, had the smallest P300 amplitudes. P300 changes are thought to reflect underlying cognitive alterations in attention and information-processing ability. The implication was that the translocation altered underlying gene expression, leading to increased risk of developing psychiatric illness. Architecturally, two breakpoints are involved, one on chromosome 11 and one on chromosome 1. The break on chromosome 11 lay “near” an important candidate gene (dopamine receptor type 2), and many genetic studies tentatively suggested that this locus may be important in schizophrenia. The well-mapped libraries of clones easily obtainable today did not exist, but the eventual mapping of chromosome 11 showed that the breakpoint there did not interrupt any then-known gene directly (a metabotropic glutamate receptor was almost 1 megabase of DNA away [10]). Thus, the search switched to chromosome 1. An unusual feature of the translocation was that it could be seen under the light microscope using phase contrast. Stains act by binding DNA but in doing so damage it. Using phase contrast kept the chromosomal material intact and allowed us to microdissect and microclone the disruption, yielding a high-quality library of breakpoint-crossing DNA [11]. This was used to isolate other clones from more general libraries in our search for underlying broken genes. To map these DNA pieces, we used a technique based on their fluorescent labeling: they will be complementary to a specific underlying chromosome region, and when “painted” onto a metaphase preparation of an individual’s chromosomes and induced to fluoresce, they “light up” at specific points (the method is now widely used and known as fluorescence in situ hybridization). If a probe spans a region that is split between two chromosomes, as in a translocation, then the fluorescence also will be split between two different chromosomes. As the DNA in the probe is complementary to the underlying DNA at the chromosome break, the probe can be examined independently to see if a gene(s) is within its structure. An unusual and novel gene complex was found to be directly disrupted by the break. The main gene was labeled as Disrupted-in-Schizophrenia-1 (DISC1), and a second, partly nested gene existed on the opposite DNA strand running antisense (probably an RNA coding gene, DISC2) [12,13]. DISC1 protein proved to be an enigma. It was brain expressed, but its function was initially unknown, with little homology to other proteins and its structure (a head domain and helical tail) not easily classified. Several questions arose. What did this protein do in the neuron itself? Did the translocation lead to reduced levels of DISC1 protein in the family? Could alteration in DISC1 be genetically associated with increased psychiatric illness

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risk in the wider population? All these have since been addressed, and evidence that DISC1 is an important neuronal gene and a risk factor for psychosis in general is steadily accumulating.

DISC1 and the neuron DISC1-containing neurons are found at high levels in specific areas of the brain also implicated in the pathology of schizophrenia and bipolar disorder (eg, the hippocampal dentate gyrus and lateral septum) but also at lower levels in other areas, including the cerebral cortex and amygdala [14]. At a more detailed level, DISC1 seems to be distributed widely in multiple types of neuronal synapses [15], and involvement in synaptic function has also been proposed through a detailed analysis of its cellular interactors [16]. DISC1 protein’s actions resemble those of so-called scaffold proteins. These bring together other proteins, allowing the resulting complex to interact in some way (eg, promoting enzymatic reactions or cell-signaling events). The number of proteins that directly bind to DISC1 is large, suggesting that it is functionally active in several different intracellular compartments, including the cytoskeleton, centrosome, and mitochondria [17–19]. One such role involves binding the protein Ndel1, which in turn binds Lis1 [20]. Mutation of the LIS1 gene leads to a severe developmental brain malformation, lissencephaly (literally “smooth brain”). In affected humans and animal models, the abnormality arises through disturbed timing of the migration of neuronal precursors in the in utero developing brain. The cerebral cortex’s normal layered structure and sulcal/gyral patterning are changed. Disrupting DISC1 alters Ndel1 binding [21], and recent elegant work using specific molecular inhibitors (RNAi) of DISC1 during the formative stages of rat brain development resulted in aberrant neuronal migration patterns [22•]. A link among DISC1, LIS1, and the motor mechanism of the neuron also has been found. DISC1 acts via a complex between Ndel1 and the protein 14-3-3F to induce a movement protein (kinesin-1) at the neuronal growth cone in the most distal part of the growing and moving axon of the precursor neuron [23]. Most recently, an analysis described how a reduction in DISC1 levels in the adult mouse brain deregulated the migration of newly formed neurons through the granule-cell layer of the dentate gyrus of the hippocampus [24•]. Clearly, DISC1 is set to play an important role in brain development. Equally interesting is another gene disrupted by a separate chromosome translocation—a t(1;16) translocation in a man with severe chronic schizophrenia. The chromosome 16 breakpoint disrupts the gene CDH8. However, more immediately interesting was that the chromosome 1 breakpoint disrupted a gene, PDE4B, that encodes a phosphodiesterase. This was important in itself; it is a good “drug target,” and its therapeutic potential has already been explored in psychiatry. Phosphodiesterases

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Table 1. Linkage studies with positive findings around the DISC1 locus

Linkage studies that used markers located within ± 5 megabase pairs of DNA from the DISC1 locus

Origin of population studied

SZ and related conditions found positive

Finland

SZ, SZ spectrum disorders

Scotland

UK/Ireland

Reference(s) and notes

MDD, bipolar disorder

Ekelund et al. [28], affected sibling pair genome scan

Bipolar disorder

Macgregor et al. [40], families affected multiple times by SZ and bipolar disorder

Schizoaffective disorder

Hamshere et al. [41], family study

UK/Iceland

Linkage studies that used markers directly at the DISC1 locus

Affective disorders found positive

Bipolar disorder, MDD

Curtis et al. [42], families affected multiple times by bipolar disorder

Taiwan

SZ, schizoaffective disorder

Hwu et al. [43], families affected multiple times by SZ

Finland

SZ, SZ spectrum disorders, schizoaffective disorder

Ekelund et al. [30,44], families affected multiple times by SZ

DISC1—Disrupted-in-Schizophrenia-1; MDD—major depressive disorder; SZ—schizophrenia.

are the main target for the antidepressant rolipram [25] and are also reported to alter memory function through downstream effects on cyclic adenosine monophosphate (cAMP) response element–binding protein [26]. It was very exciting when it also turned out to be a direct interactor of DISC1. What may occur is that DISC1 binds to PDE4B (or related phosphodiesterase proteins), thus modifying the phosphodiesterase’s catalytic activity. The DISC1/PDE4B complex is under dynamic control within the cell; it dissociates if cAMP levels are high, and the dissociated PDE4B is then susceptible to phosphorylation by another enzyme, leading to increased catalytic activity [27•]. The overall framework is probably part of a signaling pathway, possibly linking to the extracellular signal-related kinase system and neurotransmission. These are only some of DISC1’s known effects, and the literature is expanding quickly.

DISC1: the wider picture However, the question remains: is DISC1 important beyond the unusual family we have studied? The initial findings in support of a wider influence came from studies in Finland. A genome-wide scan of sibling pairs with schizophrenia showed evidence for linkage very close to DISC1 [28], and a family-based association study defined haplotypes (this indicates a group of markers across a gene rather than just one) found in association with the illness [29]. The best results occurred when a broad definition of psychosis was used to define caseness, one that included bipolar disorder and major depression. This parallels the phenotypes in the translocation family. The result was

later replicated in a second independent Finnish sample [30]. Since then, there have been positive replications by family linkage approaches and association analyses in a wide variety of populations. Table 1 and Table 2 consider the positional accuracy of linkage and that some mutations at a distance from a gene may still alter its function. In Japan, association with a gene for another direct interactor, FEZ1, has been reported [31]. The picture is not entirely resolved, as there are still perhaps too many different associated haplotypes in too many populations. A recent re-evaluation of data using the same markers throughout on a large European sample set (Hennah et al., unpublished data) may reduce the confusion. The associated phenotypes also seem to be widening, with autism-spectrum disorders adding to the list [32]. However, it is clear that clinically, DISC1 is a risk factor for schizophrenia and severe affective disorders. Thus, at the genetic level, the Kraepelinian dichotomy seems to be dissolving. This is also true for several other important genetic risk genes and really brings us back to where we started this review. There may be genes for psychosis, but other factors may influence the clinical outcome of the predisposition from no illness at all through to severe chronic schizophrenia. Finally, evidence is accumulating that DISC1 may influence specific cognitive parameters in the healthy [33] and psychiatrically ill populations with schizophrenia or affective disorders [34,35] and that this may relate to structural neuroanatomic variation in regions such as the hippocampus [36•]. Such studies are essential in that they provide an understanding of how changes at the neuronal

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Table 2. Association studies with positive findings relating to the DISC1 gene* Origin of population studied

SZ and related conditions found positive

Affective disorders found positive

North America

SZ, schizoaffective disorder

Bipolar disorder

Callicott et al. [36•], links findings to neuroanatomy; Hodgkinson et al. [45]

Finland

SZ, schizoaffective disorder, SZ spectrum disorders

Bipolar disorder, MDD

Ekelund et al. [30], association study embedded in linkage study; Cannon et al. [46], twin pair study

Scotland

SZ

Bipolar disorder

Thomson et al. [47]

China Han

SZ

Qu et al. [48]; Chen et al. [49], weak effect in females only

Taiwan

SZ

Liu et al. [35], link to deficit in sustained attention

Japan

MDD

Reference(s) and notes

Hashimoto et al. [50], link to ERK signaling and neuroanatomy, also tested patients with SZ

*Used markers directly at the DISC1 locus. DISC1—Disrupted-in-Schizophrenia-1; ERK—extracellular signal-related kinase; MDD—major depressive disorder; SZ—schizophrenia.

level can eventually translate to alterations in clinical outcome that we classify as illness.

Of mice and men A logical progression in the DISC1 story is to disrupt or knock out the homologous gene in animals (or to insert a normal or aberrant human gene into this system). This area is fraught with problems of interpretation, especially for complex psychiatric disorders [37]. However, this is not to suggest that we not study such models. Clapcote et al. [38•] induced mutations in DISC1 in mice using site-directed chemical mutagenesis. They claim that one type of mutation is associated with depressive-type symptoms in mice, whereas another generates symptoms thought to relate to those in schizophrenia. Pletnikov et al. [39•] have created a transgenic murine model that expresses a mutated form of DISC1, again with behavioral effects thought to be relevant to those seen in human schizophrenia.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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Conclusions The discovery of DISC1 highlights the important role cytogenetic abnormalities can play in pinpointing susceptibility genes for psychoses. The phenotypes associated with alterations in this one gene seem to challenge the traditional Kraepelinian dichotomy of mental illness into schizophreniform and affective disorders. Perhaps here we have a genetic susceptibility to psychotic illness, with secondary effects determining the final clinical outcome.

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Disclosures No potential conflicts of interest relevant to this article were reported.

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Millar JK, Wilson-Annan JC, Anderson S, et al.: Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000, 9:1415–1423. 13. Millar JK, Christie S, Anderson S, et al.: Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry 2001, 6:173–178. 14. Austin CP, Ma L, Ky B, et al.: DISC1 (Disrupted in Schizophrenia-1) is expressed in limbic regions of the primate brain. Neuroreport 2003, 14:951–954. 15. Kirkpatrick B, Xu L, Cascella N, et al.: DISC1 immunoreactivity at the light and ultrastructural level in the human neocortex. J Comp Neurol 2006, 497:436–450. 16. Camargo LM, Collura V, Rain JC, et al.: Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry 2007, 12:74–86. 17. Millar JK, Christie S, Porteous DJ: Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun 2003, 311:1019–1025. 18. Morris JA, Kandpal G, Ma L, Austin CP: DISC1 (DisruptedIn-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet 2003, 12:1591–1608. 19. Miyoshi K, Honda A, Baba K, et al.: Disrupted-InSchizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Psychiatry 2003, 8:685– 694. 20. Brandon NJ, Handford EJ, Schurov I, et al.: Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci 2004, 25:42–55. 21. Ozeki Y, Tomoda T, Kleiderlein J, et al.: Disrupted-inSchizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci U S A 2003, 100:289–294. 22.• Kamiya A, Kubo K, Tomoda T, et al.: A schizophreniaassociated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 2005, 7:1067–1078. Elegant and important study showing the effects of a mutated DISC1 on neuronal migration and cortical development and the use of RNAi as a molecular tool. Truncating DISC1 (although, contrary to the authors’ suggestion, this may not be happening with the translocation) changes neurite outgrowth in vitro and proneuron migration in the developing brain in vivo, leading to an altered pattern of neuronal layering in the cerebral cortex. The technical expertise shown in this paper is of a very high quality. 23. Taya S, Shinoda T, Tsuboi D, et al.: DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. J Neurosci 2007, 27:15–26. 24.• Duan X, Chang JH, Ge S, et al.: Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 2007, 130:1146–1158. DISC1’s part in adult neuronal genesis is a hot topic for psychiatrists given the number of psychotropic medications that seem to influence this mechanism. This paper refines the migration hypothesis by studying adult brain neurogenesis and posits that DISC1 may relay position signals to migrating proneurons. This finding also provides a link to another gene, NPAS3 (not mentioned in the paper), also disrupted by chromosomal abnormality in schizophrenia, which alters adult neurogenesis. 25. Kanes SJ, Tokarczyk J, Siegel SJ, et al.: Rolipram: a specific phosphodiesterase 4 inhibitor with potential antipsychotic activity. Neuroscience 2007, 144:239–246. 26. Bourtchouladze R, Lidge R, Catapano R, et al.: A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proc Natl Acad Sci U S A 2003, 100:10518–10522.

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Millar JK, Pickard BS, Mackie S, et al.: DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 2005, 310:1187–1191. Key article that shows how DISC1 interacts with another protein, PDE4B, whose gene is disrupted by a separate chromosome abnormality. The cellular levels of cAMP alter the dissociation-association kinetics of the DISC1/PDE4B complex; dissociated PDE4B is then phosphorylated. PDE4B is the main target for the antidepressant rolipram. The paper also shows that in lymphoblastoid cell lines from carriers of disrupted DISC1 and PDE4B, there is a reduction of each protein by about 50% of control cell lines—haploinsufficiency. 28. Ekelund J, Lichtermann D, Hovatta I, et al.: Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. Hum Mol Genet 2000, 9:1049–1057. 29. Hennah W, Varilo T, Kestila M, et al.: Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 2003, 12:3151–3159. 30. Ekelund J, Hennah W, Hiekkalinna T, et al.: Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol Psychiatry 2004, 9:1037–1041. 31. Kockelkorn TT, Arai M, Matsumoto H, et al.: Association study of polymorphisms in the 5’ upstream region of human DISC1 gene with schizophrenia. Neurosci Lett 2004, 368:41–45. 32. Kilpinen H, Ylisaukko-Oja T, Hennah W, et al.: Association of DISC1 with autism and Asperger syndrome. Mol Psychiatry 2008, 13:187–196. 33. Thomson PA, Harris SE, Starr JM, et al.: Association between genotype at an exonic SNP in DISC1 and normal cognitive aging. Neurosci Lett 2005, 389:41–45. 34. Burdick KE, Hodgkinson CA, Szeszko PR, et al.: DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005, 16:1399–1402. 35. Liu YL, Fann CS, Liu CM, et al.: A single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1: association with impairment of sustained attention. Biol Psychiatry 2006, 60:554–562. 36.• Callicott JH, Straub RE, Pezawas L, et al.: Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci U S A 2005, 102:8627–8632. Interesting results relating alterations in brain structure to DISC1. A haplotype was associated with schizophrenia in a family sample; within this, a single nucleotide polymorphism was overtransmitted in schizophrenia and associated with altered hippocampal size in healthy individuals. Reveals the power of integrating genetic and imaging approaches. 37. Low NC, Hardy J: What is a schizophrenic mouse? Neuron 2007, 54:348–349. 38.• Clapcote SJ, Lipina TV, Millar JK, et al.: Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 2007, 54:387–402. Specific mutations induced in differing parts of one exon of the murine Disc1 gene. The actual site of mutagenesis seems to dictate the behavioral outcome, with one mutation giving rise to a phenotype suggestive of depression, another to schizophrenia. Both mutant forms of mouse Disc1 showed reduced mouse PDE4B binding. Reversal of some phenotype anomalies by haloperidol and clozapine in the “schizophrenia” mutant and by buproprion (but not rolipram) in the “depressive” form. 39.• Pletnikov MV, Ayhan Y, Nikolskaia O, et al.: Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry 2008, 13:173–186. Another murine model, this time using a system that can “switch on and off” an inserted copy of a mutated human DISC1 gene with expression restricted to forebrain. Mouse had certain characteristics thought to be synonymous with schizophrenia. The study illustrates the power of this method of controlled forced expression of a mutant gene in site-specific brain areas.

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