Mike Fry
James Davis
Ponciano Hernandez
Psychobiology
5/7/01

The Genetics of Schizophrenia

Introduction

By Mike Fry

Schizophrenia is one of the most bizarre and potentially 
devastating of all mental disorders, characterized by a constellation 
of symptoms including disturbances in thought content and form, 
perception, affect, sense of self, volition, interpersonal 
relationships, and psychomotor behavior (Richardson 2001). The 
symptoms are manifested in two classifications: Positive, class 1, 
and Negative, class II (Survey of Social Science, 1993). Positive 
symptoms generally include the more active manifestations of abnormal 
behavior, or an excess or distortion of normal behavior; these 
include delusions and hallucinations. Negative symptoms involve 
deficits in normal behavior in such areas as speech and motivation 
(Durand 2000). Examples of such negative effects would be a lack of 
normal emotional responsiveness, thought0blocking, inadequate social 
behavior and inadequate self-care or personal hygiene behaviors 
(Richardson 2001). Disorganized symptoms include rambling speech, 
erratic behavior, and inappropriate affect. A diagnosis of 
schizophrenia requires disturbance for six months accompanied by one 
month of active phase symptoms, which are two or more positive, 
negative, and/or disorganized symptoms (DSM-IV). Diagnosis is made 
based upon the prevalence of the most dominant symptoms. Three 
divisions of schizophrenia have persisted; catatonic (alternate 
immobility and excited agitation), hebephrenic (disorganization; 
silly and immature emotionality), and paranoid (delusions of grandeur 
or persecution) (Durdan 2001). Behaviors and functional edifices can 
very widely between patients and even in the same patient at 
different times.
The causality of Schizophrenia is not clear leading the way for 
numerous speculative theories as to the possible antagonist. The 
developmental theory asserts that if a person fails to form strong 
interpersonal relationships during childhood then schizophrenia will 
develop. The interpersonal theory places an even greater emphasis on 
the environment claiming that the negative opinions of others can 
cause the mental illness to form. The environmental model insinuates 
that the combination of both a negative family life coupled with 
physical factors can lead to schizophrenia development. The 
Socio-cultural model claims that societal factor's intensify symptoms 
in vulnerable people. There is also some evidence of a 
"schizoid-virus" that can infect people, usually during fetal 
development. A higher incidence of schizophrenia in children whose 
mothers had influenza during the second trimester, when the fetal 
brain is developing, supports this hypothesis (Richardson 2001). It 
is also interesting to note that a higher incidence of schizophrenia 
is reported among urban men compared to their rural peers 
9incicatinga viral component (Durand 2001). There has also been 
considerable evidence supporting a biological cause. Studies show 
that most schizophrenics have larger lateral ventricles indicating 
the under development of other brain centers. Over active dopamine 
release has also been suggested citing the fact that anti-psychotic 
medications, which inhibit D2 receptor have proven quite effective in 
alleviating schizophrenic symptoms. However this theory has lost 
credibility in recent years with the improved effectiveness of drugs 
such as Clozapaine, which are less powerful dopamine inhibitors but 
also mediate the release of Serotonin. There is overwhelming evidence 
for a strong genetic component to the etiology of schizophrenia.



The genetics

Evidence has shown that there is a strong genetic component to 
schizophrenia. Family studies compare the frequency of schizophrenia in 
relatives of cases with the frequency in a group of controls drawn from 
the general population. The lifetime morbid risk for Schizophrenia in 
the world wide population is about 1 % and family studies have shown 
that the relatives of schizophrenics are at significantly increased 
risk of the disorder, the risk increasing with genetic closeness of the 
relationship (Remschidt 2001). These phenomena can be observed in the 
graph, which summarizes the results that Gottesman (1991) acquired 
after combining the results of 40 family studies of schizophrenia.


 

A study done in 1996 of a rural Irish population reportedly found the 
risk for schizophrenia among first-degree relatives of schizophrenics 
to be 6.1 % and the risk among sibs was 8.3 % compared to the 
population, which had a risk of 1.4% (OMIM 2001). Kallmann examined 
relatives of over 1,000 schizophrenics, in 1938. His observations 
showed that the more severe a parent's schizophrenia, the more likely 
the children were to develop it. Kallmann also observed that all forms 
of schizophrenia were seen within families, which indicates that a 
person does not inherit a predisposition for a subtype of 
schizophrenia. Rather a person can inherit a general predisposition for 
schizophrenia that can manifest in the same form or different form of 
an affected family member (Durand 2000). Taking this line of reasoning 
one step further an article by Varma (1997) reported a study of 1089 
first-degree relatives (FDR) of schizophrenics and 1137 controls. Their 
research showed an increased risk of FDR's developing schizophrenia, 
schizoid-personality disorder, and depressive disorder compared to the 
controls. Other disorders also found in lesser frequency, were bipolar 
disorder, paranoid personality disorder, anti-social personality 
disorder and neurotic disorders. Varma used these results to propose 
that the different classification of mental disorders actually lie 
along a continuum from unipolar to bipolar disorder to schizoaffective 
psychosis and right up to schizophrenia (Varma 1997). However, the 
majority of the evidence tends to support Kraepelin's theory that 
schizophrenia and manic-depressive psychosis are two distinct 
disorders.
In order to clarify whether the evidence found in familial 
studies is due to shared genes, shared environment, or both, it is 
necessary to examine data from adoption and twin studies. Adoption 
studies have confirmed a genetic contribution to the etiology of 
schizophrenia. Kendler & Gruenber's 1994 adoptee study showed that 
14.4% of 209 biological relatives of adopted away schizophrenics 
developed the disorder themselves, compared to just 3% of 229 adoptive 
relatives of schizophrenics and relatives of control adoptee. Other 
such tests have consistently found higher rates of schizophrenia among 
biological relatives compared with adoptive relatives or controls. Twin 
studies have showen an increased concordance rate among monozygotic 
(MZ) twins compared to Dizygotic (DZ) controls. A twin study by Farmer 
(1987) found concordance rates for MZ twins to be almost 50% and for DZ 
to be considerably less at 7%. Further more twin studies shown that the 
environment for child rearing does not mediate the development of 
schizophrenia. In a study of MZ twins raised apart results showed a 
concordance rate of 58%, which is slightly higher than that seen in 
twins raised together (Remschidt 2001). In another fascinating twin 
study Mirsky (1984) reviewed the study of the famous Genain 
Quadruplets, four women who are schizophrenics. Though the four ladies 
are genetically identical, and were raised in the same dysfunctional 
household, the actual expression of the illness differs among the four. 
Each of the women has responded differently to antipsychcotic 
medication over the past years. The Quadruplet study typifies the point 
that while heredity is very important many other factors besides 
genetics may contribute to how the predisposition to schizophrenia is 
expressed. The Quadruplets serve as an example of the fact that from a 
familial perspective the subtypes of schizophrenia are not 
etiologically distinct syndromes. The evidence suggests that genetic 
factors account for about 70% of the liability to schizophrenia 
(Lenox).
The fact that genetically identical MZ twins do not show 100% 
concordance implies that the transmitted genes show incomplete 
penetrance. This is confirmed by the fact that both twins share an 
equal risk of having an affected offspring (Durdan 2000). Heston 
postulated in 1970 that if the prevalence of a schizoid state were 
analyzed as a spectrum encompassing a broad area of mental disorders 
the results would statistically support an autosomal dominant 
inheritance pattern (OMIM 2001). He cited the fact that FDR's of 
Schizophrenics do not have a high incidence of clinically diagnosable 
schizophrenic if mental disorders were considered as a whole, such as 
schizoid personality and bipolar disorder, the inheritance pattern 
becomes much more obvious. Heston's hypothesis has lost credibility with 
the times and it has been statistically proven that a polygenic: model 
or a single gene model does not adequately describe the mode of 
inheritance of schizophrenia (Remschmidt 2001). Other modes of 
inheritance known as multifactoral traits, which involve many genes of 
small effect with or without environmental effects, have been purposed 
however; a clear mode of inheritance has not yet been discovered.
Penrose and others have conducted studies, which have shown that 
genetic anticipation occurs in families with schizophrenia (OMIM 2001). 
Anticipation refers to the process in which the disease becomes more 
severe and presents earlier in subsequent generations, a phenomenon 
that has been described in families with schizophrenia (Remschidt 
2001). Anticipation was observed to be even more strikingly apparent in 
pedigrees with three successive generation affected (OMIM 2001). 
Anticipation is caused by a trinucleotide repeat expansion. 
Unfortunately repeat expansions can be detected, although not located
Linkage is established when a genetic marker and a disease are 
found to occur together more frequently than would be expected by 
chance. Linkage is estimated using the lod (log of the odds) score 
method where the lod score is calculated for a range of possible values 
of the recombination fraction (RF). A lod score of 3 or more is taken 
as acceptable evidence that linkage is present, while a lod score of -2 
or less excludes linkage. The current trend in thinking is that 
schizophrenia is a multifactoral trait. There has been confirmed 
evidence of vulnerability of locus 6p with a lod score of 3.51 
accounting for up to 30% of pedigrees, and from another study that 
found linkage on 3p and 8p (Lennox). However, other studies have 
refuted these findings testifying to how complex linkage test can be. 
In a summary of the findings by Infinite Technologies genetic linkage 
of multiple family studies was found to exist for chromosomes 5q, 6p, 
8p, 10p, 13p, 18p, and 22p. This same article also suggested that case 
control studies, which have provided the strongest evidence for 
involvement of two candidates genes, show linkage for dopamine 
receptors on (DRD3) (chromosome 3P 13.3) and serration receptor (5HT2a) 
(chromosome 13q 14-Q-21). Lod scores of three or more have been 
independently found on at least eleven other gene sites according to 
the OMIM web page (OMIM 2001).
Genes of small effect may be detectable using association studies 
that investigate whether a particular marker is more common in a sample 
of unrelated schizophrenics. Studies, which focused on the association 
with ABO blood group accidentally, found support for an association 
between schizophrenia and HLA A9, although the effect is small 
(Remschmidt 2001). Another study Reported to the OMIM found an area 
located on 6p2l.3, which was highly associated with schizophrenia.

There is compelling evidence for a genetic component to 
schizophrenia. However, this same evidence also indicates that there 
are certain environmental factors that contribute to the etiology of 
schizophrenia. For example, MRI scans show that FDR's often have 
similar brain abnormalities compared to their affected relatives 
(Durdan 2000). A recent study found that transcript-encoding proteins 
involved in the regulation of presynaptic function were decreased in 
all subjects with schizophrenia suggesting that subjects with 
schizophrenia share a common abnormality in presynaptic function. 
Another study also reported finding abnormalities with the pyramidal 
cells of the basal ganglia (OMIM 2001). Many hypotheses have been made 
as to what these environmental factors might be which cases 
schizophrenia to appear in some people but no others. It has been 
suggested that insults to the embryo during the second trimester when 
brain development is occurring during the first years of life when brain 
maturation is most noticeable may be responsible. The current model of 
the causation of schizophrenia is very similar to that, used to 
understand cancer where several "hits" may lead to its phenotypic 
expression (New England Journal of Medicine).  

References

1.	Barlow & Durand "Abnormal Psychology" (2000)
2.	Remschmidt, Helmut; "Schizophrenia in children and adolescents" 
(2001)
3.	Lennox, Belinda & Jones, Peter "The Causes of Schizophrenia-
What's New?" (1998)
4.	www.OMIM.com OMIM Entry 181500 Schizophrenia; Sczd. (2001).
5.	Parnas, Schulsinger, Schulsinger, Mednick, Teasdale "Behavioral 
precursors of Schizophrenia spectrum.  A prospective study"  
(2001) 
6.	Varma, Shashjit "Genetics of Schizophrenia and Affective Disorder 
– An Overlap" (1997)
7.	www.google.com "ask the experts on Schizophrenia" 1998
8.	"Molecular Genetics of Schizophrenia and Depression.)  National 
Institute of Mental Health (1998)
9.	The New England Journal of Medicine – February 25, 1999 – Vol. 
340, No. 8  "understanding the Causes of Schizophrenia
10. Genetic Evidence www.google.com

James Davis Psyc Bio paper #2 
 
DNA or, deoxyribonucleic acid is the genetic material that people 
receive from their mother and father. DNA contains all of the codes for 
the protein your body is made up of and regulatory proteins that you 
need to function. DNA is contained in the nucleus of all of your cells, 
but protein production occurs on the ribosomes of the endoplasmic 
reticulum outside the nucleus. (Audesiric,2000) In order for the DNA's 
code to be read and used, MRNA transcription must occur. 
 
MRNA is another type of nucleic acid whose job is to copy the code 
(from the DNA) for the protein that needs to be produced and bring it 
to the ribosomes of the endoplasmic reticulum. Proteins are made up of 
long chains of amino acids. Each amino acid corresponds to a three-
nucleotide base. TRNA reads the MRNA and builds the protein one three-
nucleotide base at a time. If you add or delete a nucleotide in the 
sequence, the entire code changes from that point on and does not make 
the correct protein. (Audesiric, 2000) 
A group of investigators has found a repeating three-nucleotide base 
(CAG) in a gene on chromosome 22 that controls the flow of potassium 
ions into brain cells. This base repeat was significantly longer in the 
schizophrenic group than in the control group. (Travis 1997) Similar 
repeating nucleotide bases have been shown to be the cause of 
Huntington's disease. (Travis, 1997) Investigators warn that more 
research needs to be done to fully understand the significance of this 
finding. 
 
When an affliction is said to have a genetic basis, it is linked to a 
mistake in the code common to all those with the affliction and 
different from those who are not afflicted.(Audesiric,2000) Until 
recently, detecting a glitch in the code was almost impossible; 
consequently Twin and adoption studies were used to determine the 
heritablity of schizophrenia. If monozygotic twins share 100% of their 
genes and dizygotic twins share (on average) 50% of their genes then 
one would expect a purely genetic disease to be concordant with both MZ 
twins and not all DZ twins. (Mcguffin 1995) There are statistically 
significant correlations for schizophrenia among family members, but 
not for the disease to be purely genetic. 
 
Mcguffin summarized Gottsman and Shields liability/ threshold model to 
explain the transmission of schizophrenia. 
 
"The assumption is that liability to develop the disorder is normally 
distributed in the population and that this distribution reflects the 
additive effects of several different genes plus environmental factors. 
Only those individuals whose liability at some time exceeds the 
threshold manifest the disease. Relatives of schizophrenics have on 
average an increased liability compared to the general population and 
hence more relatives lie beyond the threshold for manifesting the 
disorder"(Mcguffin 1995) 
This model takes into account environmental as well as genetic factors. 
This model supports the polygenetic theory of schizophrenia. It appears 
that not only does schizophrenia arise from gene-environment 
interaction but from multiple genes acting in an additive fashion. 
 
Schizophrenia is a conundrum. Its diversity makes it difficult to 
diagnose let alone find a cause. We do know through twin and adoption 
studies that it seems to be a heritable condition but not in the strict 
Mendelian segregation sense. Having a schizophrenic relative increases 
the likelihood of you developing the condition but there seem to be 
factors involved that we have not been able to identify as yet. With 
the advent of the human genome map It has been shown that certain gene 
mutations have an effect on schizophrenia as well. The human genome 
project is a step towards a better understanding of our genetic "Hard 
Drive", and its relation to schizophrenia and other debilitating 
conditions, but understanding the genetics is only half of the 
equation. We have but only pieces of the puzzle that is schizophrenia. 
In order to fully understand and pin point causes of these conditions 
we must develop better environmental controls, and in many cases 
control the genetics and test the environment. 
 
 
Audesiric, Teresa, (2000) Life on Earth New Jersey, Prentice hall,INC. 
Hodgkinson, Kathleen A, et al. (2001) Genetic counseling for 
Schizophrenia in the era of molecular genetics. Canadian Journal of 
Psychiatry. Vol. 46issue 2, p123. 
 
Mcguffin, Peter; Owen, Michael J. (1995) Genetic Basis of 
Schizophrenia. Lancet, Vol. 336 issue 8976, p678 
 
Travis, J (1997). Repeating DNA linked to Schizophrenia. Science News, 
Vol.152 issue 19, p244.

Ponciano Hernandez

A Brief Look at Schizophrenia

     The cause of schizophrenia is not confined to a single specific 
factor. In fact, many factors, such as disease(Munk-Jorgensen & 
Ewald,2001), low birth-weight(Kunugi, Nanko, & Murray,2001), and 
genetics(Tsuang, Stone, & Faraone, 2001) are believed to be linked with 
schizophrenia. Schizophrenia is defined as a serious mental disorder 
characterized by disordered thoughts, delusions, hallucinations and 
often bizarre behavior(Carlson, 1998). This disorder may be traced back 
to ancient times, suggesting that it may be inherited(Carlson,98). In 
the following discussion, I will try to show how the previously 
mentioned factors may play a part in schizophrenia.
     One proposed cause of schizophrenia is disease. In a report by 
Jorgensen & Ewald, using data covering a ten year period, strong 
inferential evidence suggests that an influenza infection can cause 
damage to the developing brain making it more susceptible to 
schizophrenia. In two different studies, data implied that the most 
damage to the brain occurred during the second trimester(Tsuang et al & 
Jorgensen and Ewald). Areas of development in the second trimester are 
the hippocampus, cingulate gyrus, and prefrontal lobe (Tsuang et al). As 
a result, neural networks in these area may not be functioning 
properly.
     Another cause tied to schizophrenia is low birth-weight. Kunugi, 
Nanko, and Murray, using data from a Mednick et al., reported that 
children born to schizophrenics had a higher incidence of low birth-
weight. Also, data from a more recent study also showed those 
trends(Kunugi et al). However, other factors were also associated, such 
as higher pre-term birth and being small for gestational age. These 
correlations were seen more in children born to women with 
schizophrenia than those without.
     If traits such as eye and hair color are passed by our genes from 
one generation to the next, then why not schizophrenia? The last factor 
connected to schizophrenia is heredity. Kunugi et al believe that low 
birth-weight may be associated with schizophrenia. In a commentary by 
Rall(1998), based on a study conducted by Kety et al, he reported that 
incidence of schizophrenic disorders was higher in biological relatives 
than in non-biological relatives of adoptees. This may suggest there is 
a genetic component to the disorder. 
       Although the precise cause of schizophrenia is not known, 
research indicates that a variety of factors play a role in the 
manifestation of schizophrenia. However, which influences which, is not 
known. Is it disease, low birth-weight, or genetics which causes the 
disorder? For now, the question is a difficult one to answer. But 
through extensive research, we may arrive closer to a conclusion one 
day. If I had to say which factors were the agents responsible for the 
disorder, I would have to answer disease and genetics. Through disease, 
I believe, mutation occurs and by reproduction we pass our genes along.

References
     Carlson,N. (1998). Physiology of Behavior. Allyn and Bacon, 
Boston.
     Kunugi, H, Nanko,S & Murray, R.M. (2001). Obstetric complications 
and schizophrenia: prenatal underdevelopment and subsequent 
neurodevelopmental impairment. The British Journal of Psychiatry, Apr, 
v178, pS25-S29.
     Rall, J.E. (1998). Where are the genes specifying mental illness? 
The Journal of Nervous and Mental Disease, v186, p722-723.
     Tsuang, M, Stone, W, & Faraone,S. (2001). Genes, environment, and 
schizophrenia. The British Journal of Psychiatry, Apr, v178, pS18-S24.
     Jorgensen, P, & Ewald, H. (2001). Epidemiology in neurobiological 
research exemplified by the influenza-schizophrenia theory. The British 
Journal of Psychiatry, Apr, v178, pS30-pS32.

Copyright © 2001, Dr. John M. Morgan, All rights reserved - This page last edited 8 May, 2001
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