SCHIZOPHRENIA AND THE 
       GENETIC FACTORS IMPLICATED IN ITS EXPRESSION

                       Aaron Hogue
                      Psychobiology
                       Spring 1997


INTRODUCTION
     Schizophrenia is a psychosis characterized by
hallucinations, social withdrawal, irrational thought
processes, delusions of persecution, and a number of
other behavioral abnormalities (Carlson, 1994). It is
found throughout the world and affects as much as 1% of
the population (Carlson, 1994).  For some time there has
been strong indications that schizophrenia is in part due
to genetic factors. Family and twin studies have shown a
greatly increased risk of the disease in family members,
ranging from 2.9% risk in first cousins to 57.7% risk in
the identical twin of schizophrenics (Tsuang, 1991). 
Various genetic models have been proposed to explain this
concordance, but the currently favored models tend to be
multiple locus models such as multifactorial polygenic
(unspecified number of loci) and Limited Loci models
(Tsuang, 1991).  Given the variability in the phenotypic
expression of schizophrenia in families with a history of
schizophrenia, it is likely that some form of
environmentally influence, multiple loci model is the
most accurate.  The focus of this paper is to review some
of the current research on the role of specific areas of
the genome in the development of schizophrenia.

REVIEW
     One area of the genome that may play a role in
schizophrenia is the pseudoautosomal portion of the X and
Y chromosomes.  This was in part suspected due to the
high occurance of cytogenic abnormalities, but additional
evidence has been found in the distribution of the
disorder in the offspring of schizophrenics (Gorwood,
1992).  If genes partly responsible for schizophrenia are
located there, it is expected that the disorder will
occur more frequently in same sex offspring when
transmitted paternally.  This is, in fact, the case.  As
to the precise location of the gene(s) in this region,
however, little is known.  There is some indication that
it may be more centrally located, closer to the
centromere (Gorwood, 1992).
     Another chromosomal area that has been implicated is
a region of chromosome 5.  These findings were initially
based on a single family in which the members of the
family that exhibit schizophrenia are the only ones that
have partial trisomy of an inverted sequence on
chromosome 5 (Bassett, 1988).  Those members who have the
normal or inverted sequence, but lack the third copy, do
not exhibit the symptoms of the disorder (Bassett, 1988). 
Other researchers have found mixed results, with some
studies showing no clear connection, while others have
obtained data to support the original findings (Carlson,
1994).  Thus, if this region of chromosome 5 is involved
in schizophrenia, it is likely one of many.
     One recent development in the genetics of
schizophrenia is the possible role of phospholipid
abnormalities in some schizophrenics (Horrobin, 1995). 
Schizophrenics in which the negative symptoms predominate
have been found to show abnormally low levels of
docosahezaenoic (DHA) and arachidonic (AA) acids in the
phospholipids (Horrobin, 1995).  A couple of genes are
suspected to be involved in this, though abnormalities in
the promoter region of one in particular has been
implicated.  The gene in question is the one that codes
for the production of cytoplasmic phospholipase A2
enzymes (cPLA2) which are responsible for the removal of
certain phospholipids within the brain (Horrobin, 1995). 
Of particular interest is the fact that there are several
alleles implicated in this highly polymorphic region of
chromosome 1.  Of  those schizophrenics with high
probabilities for low DHA and AA levels, 100% had alleles
in the A7-A10 region and none in A1-A6 region, compared
with 8% and 92% respectively in a normal population
(Horrobin, 1995).
     There are a number of important ramifications of
these findings.  First, the high number of potential
allelic combinations in this gene can help explain why
there is such variability of schizophrenia in families
with a high incidence of the disorder.  In other words,
because of the large number of potential combinations,
there may be a variety of ways in which this gene can be
expressed phenotypically.  Second, cPLA2 enzymes are one
of many interacting components in the maintenance of the
cell membrane phospholipid system.  Defects in other
enzymes, such as acylating enzymes (which function in the
insertion of DHA and AA into phospholipids), could have
dramatic effects on whether schizophrenia is actually
expressed (Horrobin, 1995).  Lastly, phospholipids offer
an ideal place for the interaction of genetic and
environmental factors (such as diet), which can also go a
long way in explaining much of the variability in the
development of schizophrenia.
     In addition to structures on the cell surface,
structures within the cell have also been implicated in
schizophrenia.   Arnold et al. found that two
microtubule-associated proteins (MAP2 and MAP5) showed a
severe lack of immunoreactivity in schizophrenic patients
(Arnold, 1991).  This failure in immunoreactivity of MAP2
and MAP 5 proteins within the subiculum and entorhinal
cortex of 83% of the schizophrenic patients was in stark
contrast with both the normal controls and dementia
patients studied.  No normal patients and only 17% of
dementia patients reviewed showed any indication of a
reduced immunoreactivity (Arnold, 1991).  Whether these
structural defects are due specifically to genetic
factors, or alterations having occurred after the fact is
hard to say.  More work is necessary to determine
precisely where the problem lies, though there is
evidence that it is at least not due to the
administration of neuroleptics (Arnold, 1991).
     Back on the genetics front, two independent studies
found that the maximum size of CAG/CTG repeats is higher
in schizophrenics than controls (Bowen, 196).  Using
repeat expansion detection, several other studies have
since replicated these findings with positive results
(Bowen, 1996).  Thus, there is strong evidence that
CAG/CTG repeats at some locus is involved in
schizophrenia.  However, a recent analysis of 45
polymorphic loci with five or more repeats failed to
isolate the gene responsible, though many other possible
loci remain to be studies (Bowen, 1996).
     Finally, no study of schizophrenia would be complete
without discussing the role of dopamine receptors.  It is
well known that one of the most effective ways to manage
the symptoms of schizophrenia are through the
administration of neuroleptics which block dopamine
receptors.  Only recently has evidence emerged as to
specific genetic factors involved.  Specifically,
researchers have found that those who have a serine to
glycine point mutation in residue 9 (corresponding to the
Bal I RFLP), have twice the risk of getting schizophrenia
compared with those who lack this mutation (Lundstrom,
1996).  When variants of the dopamine D3 receptors coded
for by this region were assayed, it was found that
Ser9Gly mutant homozygotes exhibited a significantly
higher binding affinity for dopamine than the
heterozygote of wildtype (Lundstrom, 1996).  Thus,
further evidence has been found that directly links a
genetic abnormality with the expression of schizophrenia. 

     Much more remains to be done to solve the riddle of
schizophrenia.  This was just a small part of the bigger
puzzle that must be put together to truly understand how
schizophrenia comes about and what factors mediate its
expression.  As it was mentioned in the beginning of this
paper, no single gene is likely responsible for all cases
of schizophrenia.  In reality, it is likely due to a
number of interacting environmental and genetic factors. 
What I have presented here show just some of what those
genetic components may be.


                    LITURATURE CITED

CARLSON, NEIL R. 1994.  Physiology of behavior.  Allyn
and Bacon, Needham Heights, Massachutes, United States,
542pp.

TSUANG,M.T., M.W. GILBERTSON, and S.V. FARAONE.  1991. 
The genetics of schizophrenia: Current knowledge and
future directions.  Schizophrenia Research, 4:157-171.

GORWOOD, PH., M. LEBOYER, T. D'AMATO, M. JAY, D. CAMPION,
D. HILLAIRE, J. MALLET, and J. FEINGOLD.  1992.  Evidence
for a pseudoautosomal locus for schizophrenia I: A
replication study using phenotype analysis.  British
Journal of Psychiatry, 161:55-58.

HORROBIN, D.F., A.I.M. GLEN, and C.J. HUDSON.  1995. 
Possible relevance of phospholipid abnormalities and
genetic interactions in psychiatric disorders: The
relationship between dyslexia and schizophrenia.  Medical
Hypotheses, 45: 605-613.

ARNOLD, S.E., V.M.-Y. LEE, R.E. GUR, and J.Q.
TROJANOWSKI.  1991. Abnormal expression of two
microtubule-associated proteins (MAP2 and MAP5) in
specific subfields of the hippocampal formation in
schizophrenia.  Proc. Natl. Acad. Sci. USA, 88:10850-10854.

BOWEN,T., C. GUY, G. SPEIGHT, L. JONES, A. CARDNO, K.
MURPHY, P. MCGUFFIN, M.J. OWEN, and M.C. O'DONOVAN. 
1996.  Expansion of 50CAG/CTG repeats excluded in
schizophrenia by application of a highly efficient
approach using repeat expansion detection and a PCR
screening test.  Am. J. Hum. Genet., 59:912-917.

LUNDSTROM, K., and M.P. TURPIN.  1996. Proposed
schizophrenia-related gene polymorphism: Expression of
the Ser9Gly mutant human dopamine D3 receptor with the
Semliki Forest Virus system.  Biochemical and Biophysical
Research Communications, 225: 1068-1072.

BASSETT, A.S., B.C. MCGILLIVRAY, B.D. JONES, and J.T.
PANTZAR.  1988. Partial trisomy chromosome 5
cosegregating with  schizophrenia.  Lancet, 1:799-801.

Copyright © 1997, Dr. John M. Morgan, All rights reserved - This page last edited March 17, 1997
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