Chromosomal abnormalities and psychosis

The search for susceptibility genes for schizophrenia and severeaffective disorder has been enhanced by the study of cytogeneticabnormalities that disrupt genes directly. One such gene isDISCI and there is increasing evidence that it may be an importantmodulator of riskof psychosis.

INTRODUCTION

TOP

INTRODUCTION

The chromosome count of the human species was correctly ascertained50 years ago and there followed an explosion of interest inchromosome abnormalities and their medical associations. Abnormalitieswhich were visible by light microscopy of suitably stainedchromosome preparations were found in relatively common syndromes.Most notable were trisomies of entire chromosomes, such aschromosome 21 in Down’s syndrome and the various sexchromosome aneuploidies, or major deletions of parts of chromosomessuch as the short arm of chromosome 5 in cri-du-chat syndrome.There were important technological developments in the late1960s. New methods for staining chromosomes in metaphase producedbanding patterns that could be used to clearly distinguishindividual chromosomes and reliably map the position of internalchromosomal rearrangements. Altered cell culture conditionsrevealed a new form of abnormality, an X-chromosome fragilesite in men causing moderate cognitive impairment and a setof variable physical features including macro-orchidism. Thiscytogenetic marker was a pointer to the later discovery ofa large DNA repeat sequence that was methylated by cells, silencingthe expression of an underlying gene and leading to the cognitive and behavioural outcomes of the fragile-X syndrome, the mostcommon inherited cause of learning disability. These discoveriesstimulated research into the underlying neurobiology of fragile-Xsyndrome. Sometimes abnormalities are restricted to specifictissues. The ‘Philadelphia chromosome’ is a reciprocaltranslocation involving chromosomes 9 and 22 in malignant cells from chronic myeloid leukaemia. Here two genes have been brokenand the resulting fusion gene produces a chimeric and pathologicalprotein which is the target for drug therapy. Such ‘acquired’chromosomal rearrangements, occurring only in affected cells,have been crucial to understanding haematological malignanciesbut also provide a paradigm applicable to constitutional geneticdisorders, including those of psychiatry.

CYTOGENETIC ABNORMALITIES AND THE GENETICS OF SCHIZOPHRENIA

TOP

CYTOGENETIC ABNORMALITIES AND...

Schizophrenia remains an enigma but genetic components undoubtedly influence its development, with clear evidence available fromtwin, family and adoption studies. The advent of DNA-basedchromosomal markers facilitated the search for susceptibilitygenes, initially by linkage within multiply affected families.Cytogenetics played a role from the start and an early linkagestudy on chromosome 5 was stimulated by the discovery of achromosome rearrangement in a Canadian family with schizophrenia.However, most early linkage studies produced conflicting findings,perhaps as a result of locus and allelic heterogeneity. Recently,several susceptibility genes have been proposed for schizophrenia– neuregulin (NRG1) and dysbindin (DTNBP1) have considerablesupport but do not account for all the genetic risk. Othergenes must contribute and crucial clues have been provided bycytogenetic studies.

An important group of patients are those with learning disabilityand schizophrenia, an association which was originally describedby Kraepelin. The risk of schizophrenia is three times higherin people with mild learning disability than in the generalpopulation and chromosomal variants and abnormalities are increased(Doody et al, 1998). Structural magnetic resonance imagingin these individuals reveals abnormalities of the hippocampusand amygdala that are more severe than in people with schizophreniaalone and very different from people with learning disabilityalone. Chromosomal abnormalities in patients with comorbiditymay shed light on schizophrenia in general. Velocardiofacial and DiGeorge syndromes are associated with learning disabilityand usually arise from small, relatively frequent ( $~$ 1 in 4000children) deletions on the long arm of chromosome 22 (22q11deletion syndromes – 22q11DS). The associated phenotypeis highly variable with congenital heart defects occurringin approximately three-quarters of patients. Approaching 90%have a 3-Mbp deletion encompassing 30 genes. This is a truecontiguous gene syndrome with the clinical phenotype beinga consequence of reduced expression of a set of genes (haploinsufficiency).The relative risk of schizophrenia in people with 22q11DS isaround 25–30, and family linkage and candidate gene associationstudies in non-deletion schizophrenia independently point toa locus on 22q11 (Owen, 2005).

Two genes in the interval stand out through linkage and association findings as possible candidates for psychiatric outcomes – catechol-O-methyltransferase (COMT; involved in monoamine metabolism)and a mitochondrial enzyme proline dehydrogenase (PRODH). Acommon polymorphism in COMT alters the enzyme’s structureand function. Several groups have shown that COMT genotypesare related to prefrontal executive function, and a longitudinalstudy identified the low activity allele as a key variablein determining prefrontal cortical volume decline and the subsequentdevelopment of schizophrenia (Gothelf et al, 2005). Experimentsin mice deficient in Prodh suggest a role for this gene inlearning and memory through hippocampal glutamatergic systems (Paterlini et al, 2005). Furthermore, epistatic interactionsbetween Prodh and Comt were observed at the molecular and behaviourallevels; for example, Comt inhibition exaggerated the effectsof Prodh deficiency on pre-pulse inhibition, a measure thoughtto be relevant to schizophrenia. This may provide a clue asto how two key neurochemical hypotheses of schizophrenia, dopaminergicand glutamatergic, may be linked at a molecular level in 22q11DS.

DISCI AND SCHIZOPHRENIA

TOP

DISCI AND SCHIZOPHRENIA

Deletions usually remove large stretches of a chromosome butreciprocal translocations between chromosomes, in their balancedform, can break within narrow bounds and have been powerfultools in clearly identifying disrupted genes and linking theseto clinical phenotypes. Where chromosomal abnormalities areassociated with a clinical disorder in several members of thesame family or are common to several unrelated patients, a causallink is likely and can be investigated by examining the DNAstructure at and around the break (MacIntyre et al, 2003).In the late 1960s extensive population surveys conducted by the Medical Research Council in Edinburgh identified an individualwith a reciprocal translocation between chromosomes 1 and 11(+(1;11)). The segregation of this rearrangement was followedthrough a greatly extended pedigree. Clinical studies, withthe investigators masked to karyotype status, confirmed andextended follow-up reports of schizophrenia, major depression and bipolar disorder in translocation carriers but not in familynon-carriers (Blackwood et al, 2001). Subsequent analysisshowed that the chromosome 1 breakpoint directly disruptedtwo overlapping genes, termed disrupted-in-schizophrenia 1 and2 (DISC1 and DISC2). DISC2, coded on the opposite DNA strandto DISC1, is transcribed but not translated and is possiblyan RNA gene with some regulatory role (Millar et al, 2001). DISC1 encodes a novel brain-expressed protein, is an important modulator of risk for schizophrenia and severe affective disorderin people without cytogenetic abnormalities and may also influencecognition and brain structure in the general population (Table 1).A frameshift DNA mutation in DISC1, which produces reducedamounts of a truncated DISC1 protein, has been described inan American family with schizophrenia and schizoaffective disorder (Sachs et al, 2005).

View this table:
[in this window]
[in a new window]

Table 1 Studies of DISC1 linkage in schizophrenia or schizoaffective disorder and of DISC1 polymorphisms and neuropsychological and neuroimaging phenotypes in schizophrenia and the general population

WHAT DOES DISC1 DO?

TOP

WHAT DOES DISC1 DO?

DISC1 likely has a role in developing and adult brain in a rangeof cellular processes, including microtubule and mitochondrialfunction. Interacting proteins include Nudel (NDEL1), a microtubule-associatedprotein that helps maintain neuronal morphology. The Nudel/DISC1complex interacts with the protein LIS1, mutations in whichlead to lissencephaly, a disorder of neuronal migration withdisorganised cerebral cortex formation. Studies in mice ofthe DISC1 orthologue show strong hippocampal expression throughoutdevelopment as well as in the developing cortex. Peaks of expressionoccur during the maximum period of foetal neurogenesis as wellas during puberty in the mouse, and a similar distributionpattern is seen in the adult monkey brain. Such findings arein keeping with our understanding of the neuroanatomy of schizophrenia.

LINKING SCHIZOPHRENIA AND AFFECTIVE DISORDERS

TOP

LINKING SCHIZOPHRENIA AND...

Findings in the family with t(1;11) support a role for DISC1in both schizophrenia and affective disorders. Some of theobserved phenotype/genotype relationships may be related towhere DISC1 localises within neurons, with different subcellularisoform distribution in brains from people with schizophreniacompared with those with major depression (Sawamura et al, 2005).

An important new understanding of the role of DISC1 in schizophreniahas emerged from study of another chromosome abnormality ina patient with severe schizophrenia in whom a reciprocal balancedtranslocation between chromosomes 1 and 16 directly disruptedthe phosphodiesterase-4 type B gene (PDE4B). In itself thiswas interesting since the antidepressant rolipram is a directinhibitor of PDE4 proteins. However, the unexpected findingwas that the PDE4B protein forms an intracellular complex withDISC1 that appears to be regulated by cellular cyclic AMP andprotein kinase systems (Millar et al, 2005). This suggeststhat these genes link schizophrenia and mood disorders and that they may identify target proteins for possible therapeuticinterventions.

CONCLUSION

TOP

CONCLUSION

A large body of evidence has accumulated over the past few yearsto suggest that DISC1 has an important role in the developmentof psychosis. It is probable that the analysis of other rarechromosome abnormalities using increasingly powerful tools,including comparative genome hybridisation methods, will givefurther new insights into the pathogenesis of psychosis. We recommend their study as an important adjunct in psychiatricgenetics and urge clinicians and researchers to identify newpatients with such abnormalities.

ACKNOWLEDGMENTS

TOP

ACKNOWLEDGMENTS

In the past 5 years the authors have received support from theMedical Research Council, the Wellcome Trust, the Chief Scientist’sOffice of the Scottish Executive, the Health Care Trust andjoint University/Industry initiatives with Azko-Nobel (Organon)and Merck, Sharp & Dohme.

REFERENCES

TOP