The British Journal of Psychiatry (2006) 188: 501-503. doi: 10.1192/bjp.bp.106.023895
© 2006 The Royal College of Psychiatrists
Chromosomal abnormalities and psychosis
WALTER J. MUIR, FRCPsych
Division of Psychiatry
BENJAMIN S. PICKARD, PhD
Medical Genetics Section
DOUGLAS H. R. BLACKWOOD, PhD, FRCPE, FRCPsych
Division of Psychiatry, School of Molecular and Clinical Medicine,
University of Edinburgh, UK
Correspondence:
Dr Walter J. Muir, Division of Psychiatry, University of Edinburgh, Kennedy
Tower, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, UK.
E-mail:
walter.muir{at}ed.ac.uk
Declaration of Interest None.
Funding detailed in Acknowledgements.

ABSTRACT
The search for susceptibility genes for schizophrenia and severe
affective
disorder has been enhanced by the study of cytogenetic
abnormalities that
disrupt genes directly. One such gene is
DISCI and there is
increasing evidence that it may be an important
modulator of riskof
psychosis.

INTRODUCTION
The chromosome count of the human species was correctly ascertained
50
years ago and there followed an explosion of interest in
chromosome
abnormalities and their medical associations. Abnormalities
which were visible
by light microscopy of suitably stained
chromosome preparations were found in
relatively common syndromes.
Most notable were trisomies of entire
chromosomes, such as
chromosome 21 in Downs syndrome and the various
sex
chromosome aneuploidies, or major deletions of parts of chromosomes
such
as the short arm of chromosome 5 in cri-du-chat syndrome.
There were important
technological developments in the late
1960s. New methods for staining
chromosomes in metaphase produced
banding patterns that could be used to
clearly distinguish
individual chromosomes and reliably map the position of
internal
chromosomal rearrangements. Altered cell culture conditions
revealed
a new form of abnormality, an X-chromosome fragile
site in men causing
moderate cognitive impairment and a set
of variable physical features
including macro-orchidism. This
cytogenetic marker was a pointer to the later
discovery of
a large DNA repeat sequence that was methylated by cells,
silencing
the expression of an underlying gene and leading to the cognitive
and behavioural outcomes of the fragile-X syndrome, the most
common inherited
cause of learning disability. These discoveries
stimulated research into the
underlying neurobiology of fragile-X
syndrome. Sometimes abnormalities are
restricted to specific
tissues. The Philadelphia chromosome is a
reciprocal
translocation involving chromosomes 9 and 22 in malignant cells
from chronic myeloid leukaemia. Here two genes have been broken
and the
resulting fusion gene produces a chimeric and pathological
protein which is
the target for drug therapy. Such acquired
chromosomal
rearrangements, occurring only in affected cells,
have been crucial to
understanding haematological malignancies
but also provide a paradigm
applicable to constitutional genetic
disorders, including those of
psychiatry.

CYTOGENETIC ABNORMALITIES AND THE GENETICS OF SCHIZOPHRENIA
Schizophrenia remains an enigma but genetic components undoubtedly
influence its development, with clear evidence available from
twin, family and
adoption studies. The advent of DNA-based
chromosomal markers facilitated the
search for susceptibility
genes, initially by linkage within multiply affected
families.
Cytogenetics played a role from the start and an early linkage
study
on chromosome 5 was stimulated by the discovery of a
chromosome 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 considerable
support but do not account for all the
genetic risk. Other
genes must contribute and crucial clues have been provided
by
cytogenetic studies.
An important group of patients are those with learning disability and
schizophrenia, an association which was originally described by Kraepelin. The
risk of schizophrenia is three times higher in people with mild learning
disability than in the general population and chromosomal variants and
abnormalities are increased (Doody et
al, 1998). Structural magnetic resonance imaging in these
individuals reveals abnormalities of the hippocampus and amygdala that are
more severe than in people with schizophrenia alone and very different from
people with learning disability alone. Chromosomal abnormalities in patients
with comorbidity may shed light on schizophrenia in general. Velocardiofacial
and DiGeorge syndromes are associated with learning disability and usually
arise from small, relatively frequent (
1 in 4000 children) deletions on
the long arm of chromosome 22 (22q11 deletion syndromes 22q11DS). The
associated phenotype is highly variable with congenital heart defects
occurring in approximately three-quarters of patients. Approaching 90% have a
3-Mbp deletion encompassing 30 genes. This is a true contiguous gene syndrome
with the clinical phenotype being a consequence of reduced expression of a set
of genes (haploinsufficiency). The relative risk of schizophrenia in people
with 22q11DS is around 2530, and family linkage and candidate gene
association studies in non-deletion schizophrenia independently point to a
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).
A common polymorphism in COMT alters the enzymes structure and
function. Several groups have shown that COMT genotypes are related
to prefrontal executive function, and a longitudinal study identified the low
activity allele as a key variable in determining prefrontal cortical volume
decline and the subsequent development of schizophrenia
(Gothelf et al, 2005).
Experiments in mice deficient in Prodh suggest a role for this gene
in learning and memory through hippocampal glutamatergic systems
(Paterlini et al,
2005). Furthermore, epistatic interactions between Prodh
and Comt were observed at the molecular and behavioural levels; for
example, Comt inhibition exaggerated the effects of Prodh
deficiency on pre-pulse inhibition, a measure thought to be relevant to
schizophrenia. This may provide a clue as to how two key neurochemical
hypotheses of schizophrenia, dopaminergic and glutamatergic, may be linked at
a molecular level in 22q11DS.

DISCI AND SCHIZOPHRENIA
Deletions usually remove large stretches of a chromosome but
reciprocal
translocations between chromosomes, in their balanced
form, can break within
narrow bounds and have been powerful
tools in clearly identifying disrupted
genes and linking these
to clinical phenotypes. Where chromosomal
abnormalities are
associated with a clinical disorder in several members of
the
same family or are common to several unrelated patients, a causal
link is
likely and can be investigated by examining the DNA
structure 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 individual
with a
reciprocal translocation between chromosomes 1 and 11
(+(1;11)). The
segregation of this rearrangement was followed
through a greatly extended
pedigree. Clinical studies, with
the investigators masked to karyotype status,
confirmed and
extended follow-up reports of schizophrenia, major depression
and bipolar disorder in translocation carriers but not in family
non-carriers
(
Blackwood et al,
2001). Subsequent analysis
showed that the chromosome 1 breakpoint
directly disrupted
two overlapping genes, termed disrupted-in-schizophrenia 1
and
2 (
DISC1 and
DISC2).
DISC2, coded on the
opposite DNA strand
to
DISC1, is transcribed but not translated and
is possibly
an 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 disorder
in people
without cytogenetic abnormalities and may also influence
cognition and brain
structure in the general population (
Table
1).
A frameshift DNA mutation in
DISC1, which produces
reduced
amounts of a truncated DISC1 protein, has been described in
an
American family with schizophrenia and schizoaffective disorder
(
Sachs et al,
2005).
View this table:
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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
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WHAT DOES DISC1 DO?
DISC1 likely has a role in developing and adult brain in a range
of
cellular processes, including microtubule and mitochondrial
function.
Interacting proteins include Nudel (NDEL1), a microtubule-associated
protein
that helps maintain neuronal morphology. The Nudel/DISC1
complex interacts
with the protein LIS1, mutations in which
lead to lissencephaly, a disorder of
neuronal migration with
disorganised cerebral cortex formation. Studies in
mice of
the
DISC1 orthologue show strong hippocampal expression
throughout
development as well as in the developing cortex. Peaks of
expression
occur during the maximum period of foetal neurogenesis as well
as
during puberty in the mouse, and a similar distribution
pattern is seen in the
adult monkey brain. Such findings are
in keeping with our understanding of the
neuroanatomy of schizophrenia.

LINKING SCHIZOPHRENIA AND AFFECTIVE DISORDERS
Findings in the family with t(1;11) support a role for DISC1
in both
schizophrenia and affective disorders. Some of the
observed phenotype/genotype
relationships may be related to
where DISC1 localises within neurons, with
different subcellular
isoform distribution in brains from people with
schizophrenia
compared with those with major depression
(
Sawamura et al,
2005).
An important new understanding of the role of DISC1 in schizophrenia has
emerged from study of another chromosome abnormality in a patient with severe
schizophrenia in whom a reciprocal balanced translocation between chromosomes
1 and 16 directly disrupted the phosphodiesterase-4 type B gene
(PDE4B). In itself this was interesting since the antidepressant
rolipram is a direct inhibitor of PDE4 proteins. However, the unexpected
finding was that the PDE4B protein forms an intracellular complex with DISC1
that appears to be regulated by cellular cyclic AMP and protein kinase systems
(Millar et al, 2005).
This suggests that these genes link schizophrenia and mood disorders and that
they may identify target proteins for possible therapeutic interventions.

CONCLUSION
A large body of evidence has accumulated over the past few years
to suggest
that DISC1 has an important role in the development
of psychosis. It is
probable that the analysis of other rare
chromosome abnormalities using
increasingly powerful tools,
including comparative genome hybridisation
methods, will give
further new insights into the pathogenesis of psychosis. We
recommend their study as an important adjunct in psychiatric
genetics and urge
clinicians and researchers to identify new
patients with such
abnormalities.

ACKNOWLEDGMENTS
In the past 5 years the authors have received support from the
Medical
Research Council, the Wellcome Trust, the Chief Scientists
Office of
the Scottish Executive, the Health Care Trust and
joint University/Industry
initiatives with Azko-Nobel (Organon)
and Merck, Sharp & Dohme.

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Received for publication January 16, 2006.
Revision received February 26, 2006.
Accepted for publication March 3, 2006.
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