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Schizophrenia is a severe and
debilitating mental illness. People Ssuffering from schizophrenia have
the following symptoms like delusions,
hallucinations, perceptions (can be sound,
sight, touch, smell or taste) that occur in the
absence of an actual external stimulus,
disorganized speech, catatonic behaviour in
which the affected person's body may be
rigid and the person my be unresponsive. Its
onset is mainly during adolescence and
nearly 1% of the population world wide is
affected (American psychiatric association
1987). However previous data suggest a higher incidence of schizophrenia in men.
They also show an earlier age at onset, poor
medication response, poor intellectual
functioning and greater structural brain
abnormalities compared to women. Studies
have also shown that schizophrenic patients
are at a higher risk of suicide
An interplay of genetic,
biological, environmental and physiological
factors are thought to be involved in this
disorder. Familiar, twin and adoption
studies have established the significance of
genetic variability in causing affective
disorders and schizophrenia. Affective
disorders are characterized mainly by cyclic
anomalies of feeling tone-depression or
mania - whereas in schizophrenia,
anomalies of thought patterns and loss of
contact with reality are the main symptoms
(Vogel and Motulsky AG, 1997)
The mode of schizophrenia
inheritance is complex/multifactorial and
non-mendelian. Even though much work
has been done to elucidate the genetics of
schizophrenia, no susceptibility gene for
this disorder has been shown to be
associated consistently though researchers
have speculated the occurrence of a large
number of genes associated with this
illness. All the parametric and nonparametric
linkage studies done have failed
to associate a single major gene responsible
for this illness (Prasad et al, 2002). In
addition to multiple genes prenatal,
perinatal and non specific stress are
involved in creating vulnerability towards
the illness. Recent studies have also shown
subtle changes in brain structure and
function, indicate a link between disorder in
the development of the brain and
schizophrenia
Two approaches have been used
consistently for the elucidation of
susceptibility genes involved - such as
linkage and association studies. Linkage
approach involves the study of segregation
of a marker along with the disease condition
within a family. This requires a
multigenerational and multimember
affected pedigree. Only genes having a
strong effect can be detected in this
approach and those having a small
effect lie undetected
Association study is a population
based method and is an alternative to
linkage studies for detecting genes having a
small effect. Both case-control studies and
family based designs are commonly used to
detect associations (Prasad et al, 2002).
Large pedigrees are not required in
association studies but it involves a
comparison between cases and controls. It
may not always identify the gene itself but a
susceptibility gene or a gene in tight linkage
disequilibrium to the disease gene. Thus
linkage and association are two different
phenomena. Linkage is a relationship between loci, but association is a
relation between alleles or phenotypes.
(Strachen & Read, 2003)
Current research in schizophrenia
includes detection of str uctural
abnormalities in the brain, evaluation of the
effect of drugs on target receptors,
neurotransmitters and physiology of the
brain, association and linkage studies with
putative genes identified based on the
biochemical or pharmacological evidence
or candidate regions identified by genome
scan studies and role of epigenetic factors in
disease causation (Prasad et al, 2002).
Conventional post-mortem studies are used
to study the anatomy of brain of affected
people and controls along with other
sophisticated techniques like computed
tomography (CT), magnetic resonance
imaging (MRI), functional imaging and
position emission tomography (PET)
Neurotransmitters belonging to the
dopaminergic and monaminergic groups
have been implicated in the etiology of
schizophrenia (carlsson, 1988, Tamminga,
1998). Their receptors and the genes
involved in their uptake, synthesis, transport
reuptake and degradation have been found
to be involved in disease pathogenesis. The
genes involved in abnormal metabolism of
membrane phospholipids and the
phospholipase C signaling pathways are also
involved. According to the dopamine
theory, excess dopamine yields positive
symptoms of schizophrenia (Matthyse,
1973). Several studies have proved the role
of neuroleptic drugs in reducing dopamine
activity. High dopamine and HVA
concentration (Homo Vanillic Acid) in
various sub-cortical brain regions and
greater dopamine receptor densities in the
brain of schizophrenic patients have been
shown by post-mortem studies. The
negative/deficit symptoms have been
found to be associated with low dopamine
activity in the pre-frontal cortex. Five
dopamine receptors are involved in
schizophrenia (Grandy et al, 1989; Dearry,
1990; Van Tol et al, 1991) like DRD1,
DRD5, DRD2, DRD3 and DRD4. Besides
dopamine transporter gene (DAT) located
15.3on chromosome 5p involved in the
reuptake of dopamine into the pre-synaptic
terminal and Tyrosine hydroxylase (TH)
gene whose product is a rate-limiting
enzyme in the dopaminergic pathway have
been considered as possible candidates in
theetiologyschizophrenia
(Nakatome et al, 1996, Perisco and
Macciardi 1997; Jonsson et al, 1998)
Several studies have implicated the
role of neurotransmitter serotonin in
regulation of physiological effects such as
sleep, depression and body temperature as
well as abnormalities of serotonin
neurotransmission in schizophrenia and
depression. The different serotonin
receptors identified are 5HT-1, 5HT-2,
5HT-3, 5HT-4, 5HT-5, 5HT-6 and 5HT-7.
Serotonin is located in the brain, smooth
muscles and in blood platelets (Prasad et al,
2002). Also catechol-o-methyl transferase
11.2gene (COMT, 22q) which catalyses the o-
methylation of dopamine, adrenaline and
nor adrenaline (thereby inactivating them)
and also Monoaminooxidase gene (MAO)
which break down excess serotonin and
dopamine are considered as possible
candidate genes (semwal et al, 2002; Prasad
et al 2002)
Besides, genome wide scans have
shown the evidence of linkage of
chromosomes 1,2 and 7 with schizophrenia
(Hallmayer, 1999). There are also report on
the presence of schizophrenia
susceptibility alleles on chromosomes 5, 8,
11 and 20. (Hugh et al, 2001), Yan et al
(2000) reported the occurrence of a
22 21reciprocal translocation t (1;7) (p ;q ) in a
childhood - onset schizophrenia case
Epigenetics in the study of stable
alterations in gene expression that arise
during development and cell proliferation.
Epigenetic processes do not change the
information contained in the DNA ,
but modulate gene expression
through modification of metagenetic
information ie. Together with promoter
sequences and transcription factors they
modulate when and at what level genes are
expressed. Examples include DNA
methylation, histone hypo acetylation,
chromatin modification, x-chromosome
inactivation imprinting. Epigenetic
phenomenon also includes position effect
variegation, paramutation, age dependant
DNA modifications (Bestor et al, 1994;
petronics et al, 1999). Recent investigations
have shown the role of DNA sequence
var iat ion a long with epigenetic
misregulation as a critical etiopathogenic
factor (Petronics, 2004). Several studies
have pointed to the role of epigenetic
factors in the causation of complex traits
like schizophrenia. Environmental factors
have also been found to cause epigenetic
changes as evidenced by altered gene
expression in the DNA. Integration of
viruses can disrupt normal
neurodevelopmental pathways resulting in
schizophrenia (Crow, 1997; Iwahashi et al,
1998; Delisi et al, 1986)
Current trends in research of
schizophrenia involve non-parametric
method of linkage analysis using large
number of affected sib-pairs. Multiple SNP
markers from candidate genes can be
analyzed using suitable approaches and
testing for allelic, genotypic and haplotypic
association with the disease. SNPs are
powerful analytical tools and along with the
technique of DNA microarrays can help in
the identification of disease associated
SNPs/alleles |
