Genetic Perspective
Running head: SCHIZOPHRENIA
A Genetic Perspective on Schizophrenia
Shennen A. Floy
Creighton University
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Genetic Perspective
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Abstract
Schizophrenia has earned a reputation as one of the most severe and debilitating of all mental
illnesses. This chronic disorder, most commonly characterized by disordered emotions, the
presence of delusions and hallucinations, and in severe cases a victim’s total withdrawal from the
traditional world, affects approximately one percent of the population. Research has indicated a
hereditary link in the development of schizophrenia, however, the intensity of influence and
mechanism of this inheritance is still unknown. This outlook provides a general overview of the
mental disorder, including signs, symptoms, and mechanism of treatment, analyzes associated
genetic risks, and considers a representative spectrum of current research into the molecular
genetics of this devastating psychological condition.
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A Genetic Perspective on Schizophrenia
Schizophrenia, a severe and debilitating mental disorder, is generally characterized by
delusions, hallucinations, difficulty in performing activities of daily living, and inappropriate
display or total lack of emotions. Onset of symptoms generally occurs in affected individuals
between the ages of eighteen and twenty-five, with approximately one percent of the general
population affected (Owen & O’Donovan, 2003). Significantly strong prevalence of the disease
among individuals with shared genetic background indicates the possibility of a genetic linkage
in schizophrenia. Modern scientific studies indicate multiple coding regions from within the
human genome which have the potential to offer insight into the presumed heritability of the
disease. Using current explorations as a foundation, future research efforts indicate the
possibility of defining the causality of this devastating disorder either solely or primarily on
genetic background. Furthermore, genetic tests for schizophrenia may emerge with the capability
of indicating the likelihood of developing the disorder during early adulthood.
Signs and Symptoms
Indicative symptoms of schizophrenia vastly differ between affected individuals. The
disorder is clinically diagnosed by a slow but progressive deterioration in overall function (Owen
& O’Donovan, 2003). The disease is characterized by expression of inappropriate emotional
behavior, from extreme agitation and distress to total withdrawal into a catatonic state.
Schizophrenic patients are challenged by social interactions, career obligations, and personal
matters, however, under many circumstances, a schizophrenic patient may behave well within
the realm of normality, displaying little to no symptoms of his or her disorder (Owen &
O’Donovan, 2003). In addition to the lack of appropriate emotional and behavioral patterns,
many patients suffering from schizophrenia experience both delusions and hallucinations.
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Delusions represent personal beliefs which have no foundation in reality, such as a paranoia that
one is being spied on or conspired against (Mayo Clinic, 2004). Hallucinations, on the other
hand, are generally characterized by a sensual experience which does not exist. For example, a
schizophrenic patient may carry on an entire conversation with voices that no one else can hear.
The schizophrenic may even go so far as to act upon these conversations (Mayo Clinic, 2004). In
order to be diagnosed with schizophrenia, an individual must display a continuous and
progressive repetition of these and other symptoms for at least six months (Carey, 2003).
Care and Treatment Strategies
Schizophrenia affects only one percent of the population, however, individuals suffering
from the disorder account for more hospital bed occupancy than any other disease (Owen &
O’Donovan, 2003). The lifetime morbidity rate is slightly less than one percent (Owen &
O’Donovan, 2003). Treatment regimes for schizophrenia include antipsychotic medications,
individual and family therapy, rehabilitation, and community based care. Originating in the
1990s, a new generation of antipsychotic medications was developed that is effective at
managing both active symptoms, i.e. delusions and hallucinations, and passive symptoms,
including inappropriate displays or complete lack of emotions. Commonly prescribed
antipsychotic drugs include: clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa),
quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify) (Mayo Clinic, 2004).
Individual therapy includes efforts to help the affected individual cope with conflicting emotions,
control delusional thoughts, and manage complex treatment regimes. Family therapy aids family
members in understanding the consequences of a loved one’s illness, as well as how they can aid
in improving the quality of life for the schizophrenic patient. Furthermore, family members may
also be trained to monitor administration and effects of drug therapy, and to recognize possible
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signs and symptoms of relapse. Rehabilitation may be used to train a schizophrenic in the social
and vocational skills necessary for function in society (Mayo Clinic, 2004). In severe cases of
schizophrenia, patients may be placed in community living situations or group homes. Patients
with severe forms of the disorder have been shown to thrive in structured environments which
provide controlled medication distribution, well thought-out activities, regular nutrition, and
proper hygiene (Owen & O’Donovan, 2003).
Statistical Risk and Heredity
A combination of behavioral, environmental, and lifestyle factors have been shown to
increase one’s risk of developing schizophrenia. These conditions include complications during
pregnancy and delivery, delayed attainment of developmental milestones, challenges in societal
relations, urban childhood, immigration, and the use of illegal drugs, specifically cannabis
(Owen & O’Donovan, 2003). Although a variety of factors have been shown to contribute to
ones’ likelihood of developing schizophrenia, no one indicator is as strong as the genetic risk
associated with having an affected first-degree relative. Monozygotic (MZ) twins, those twins
who resulted from a shared ovum, have a forty-eight percent risk for developing this disorder if
one sibling has been diagnosed with the disease. This statistical risk can be compared to a risk of
seventeen percent for dizygotic (DZ) twins and a nine percent risk for traditional siblings (Carey,
2003). The greatly increased risk for MZ twins indicates a stronger genetic contribution over
potential environmental factors. Adoption studies have offered further proof for this theory,
demonstrating that the presence of schizophrenia in biological relatives, rather than in one’s
adoptive family, predicts the adoptee's risk for developing schizophrenia (Ingraham & Kety,
2001). The discrepancy between DZ twins and other siblings is a bit more difficult to discern as
these individuals share the same degree of genetic relatedness. The variance could potentially be
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explained by the fact that DZ twins have been studied more intently than traditional siblings.
Additional explanations might include the shared prenatal experiences and common birthing
experience (Carey, 2003). Furthermore, familial studies have indicated that parents of affected
children have a six percent risk of displaying symptoms of the disorder, while children of
affected parents have a thirteen percent risk for developing the disorder in early adulthood. This
deviation can be explained by the reduced reproductive fitness of individuals suffering from
schizophrenia (Owen & O’Donovan, 2003). Based upon these and other risk analyses, the
estimated heritability factor associated with schizophrenia has been determined to be around
eighty to eighty-five percent (Cardno & Gottesman, 2001).
Genetic Mechanisms of Inheritance
The belief that schizophrenia is at least in part genetically influenced has encouraged
additional genetic research in an attempt to explain inheritance patterns of this devastating
disorder. Complex phenotypic ratios, combined with non-specific inheritance patterns, have led
scientists to believe that schizophrenia cannot be predicted with simple Mendelian inheritance
patterns (Owen & O’Donovan, 2003). Rather, current thinking predicts either oliogenic or
polygenic contribution factors for this disorder. Oliogenic inheritance implies that a few genes
display a moderate effect on the prevalence of the disease, while polygenic inheritance patterns
include the emphasis of many genes on a small scale (Owen & O’Donovan, 2003).
Molecular genetics seeks to explain the apparent genetic connection of schizophrenia by
discovering potential DNA segments, specific genes, or entire chromosomes which play a role in
determining one’s likelihood of developing the disorder. Recent research has focused on both
linkage and association methods. Linkage studies attempt to locate chromosomal regions shared
within families afflicted by schizophrenia which are not present in unaffected individuals (Berry,
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Pal, & Jobanputra, 2003). Association studies, on the other hand, isolate specific coding regions
from within the entire genome, again seeking evidence that the genetic information provided
indicates an association to schizophrenia (Berry, Pal, & Jobanputra, 2003). Thus, individuals
studying linkage patterns isolate genetic information present only in affected individuals, while
research teams focusing on association select their subject genes from the entire genome. In
addition to linkage and association studies, additional research has focused on various
chromosomal abnormalities in search of potential genetic contributors to schizophrenia.
Linkage Studies
Linkage analysis represents directed study on genes which are present in the diseased
individual, but absent in the healthy population. Researchers performing linkage analyses seek to
identify a specific gene capable of co-inheritance with a genetic marker. Single nucleotide
polymorphisms (SNPS), the most common genetic markers, are capable of co-inheritance with
the gene in question (Kamnasaran, 2003). Using the genetic marker as a guide, variation can be
detected among test subjects and specific genetic regions can be isolated for further study.
Statistical analysis is utilized in order to determine if inheritance patterns are significant for the
specific genetic region.
Williams et al., (2003) conducted one of the most extensive linkage studies of
schizophrenic patients to date. In this study, colleagues from around the globe searched entire
human genomes of 353 sibling pairs affected by schizophrenia seeking potential genetic
similarities. Although initial research was rather disheartening as the team struggled to provide
compelling evidence and lacked the ability to replicate their findings, further study has indicated
nine regions of interest in identifying genetic links to schizophrenia. Three regions in particular,
6p24-22, 1q21022, and 13q32-34, have been identified in replication trials (Williams et al.,
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2003). In addition, initial positive findings have been identified in the 8p21-22, 6q21-25, 22q1112, 5q210q33, 10p15-p11, and 1q42 chromosomal regions (Williams et al., 2003).
Linkage studies have also provided initial evidence for the presence of decreased levels
of an essential protein kinase AKT1, in schizophrenic patients. According to Emamian, Hall,
Birnbaum, Karayiorgou, and Gogos, (2004) decreased levels of AKT1 can be accounted for by
alterations of the AKT1-GSK3β signaling mechanism in schizophrenic patients. AKT1 is
responsible for a variety of functions at the cellular level, including cell metabolism, cell
survival, and apoptosis (programmed cell death). Consequently, decreased levels of the chemical
have the potential to cause extensive physical, social, and neurological consequences
(Hallmayer, 2004).
Association Studies
Association studies, in contrast to linkage studies, focus on specific genes based on the
function of the gene as opposed to its noted popularity among schizophrenic patients.
Researchers conducting association studies select a candidate gene which has the possibility of
playing a role in the expression of schizophrenia. Genes which are most commonly studied by
association include coding regions for certain neurotransmitters including dopamine and
serotonin (Tsuang, Taylor, & Faraone, 2004).
Researchers at the Okayama University Graduate School of Medicine and Dentistry in
Japan have focused their association studies on a specific protein-coding region located on
chromosome 8p21. The research team was interested in the frizzled-3, or FZD3 region, as it is
fundamental in the formation of the neural crest, and the completion of major fiber tracts within
the central nervous system. In addition, the region also influences the signaling pathway for Wnt
ligands, ligands which help to structure embryonic patterns, regulate cell proliferation, and
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influence cortical development. Some conclusive evidence has shown that deregulation within
the Wnt-signaling pathway, mediated by the alteration of the FZD3 region, may indicate
susceptibility to schizophrenia (Katsu et al., 2004).
Chromosomal Abnormalities
Chromosomal abnormalities can result from a variety of mutations within the human
genome. These mutations include, but are not limited to, translocations and deletion. When a
translocation occurs, some portion of the genetic information on one chromosome is exchanged
with another portion of DNA from elsewhere within the organism’s genome (University of
Toronto, 2004). Translocations do not remove genetic information from the genome, but rather
place the information outside of its normal realm. Deletions, on the other hand, remove an entire
segment of genetic material and can potentially cleave important genetic information from the
organism’s genome. Both of these conditions can produce pathogenic effects, in particular
because the deletion or translocation of genetic information does not only affect the genetic
segment in question. Rather, due to the position effect, the expression and regulation of
neighboring genes might potentially be affected whenever the genome is altered (University of
Toronto, 2004). For example, if region A contained a promoter sequence which affected a
connected region B, and region B contained the code to regulate gene C, removing gene A could
cause a catastrophic influence on the function of the entire genome.
Several studies have been conducted on chromosomal abnormalities (University of
Toronto, 2004). However, currently very few studies have been able to provide conclusive
evidence for the given abnormalities’ influence on the emergence or expression of schizophrenia.
Some of the studies which show the most promise for success include research on the following
chromosomal regions: the t (1; 11) reciprocal translation and deletion on chromosome 22q11.
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The t (1; 11) represents a translocation which has been shown to directly correlate with
the prevalence of schizophrenia in a large Scottish Family (Millar et al., 2000). Specific genetic
mechanisms of the translocation appear to indicate that an exchange between a small amount of
genetic material from chromosome 1 and a large amount of material from chromosome 11
occurs. The translocation is complete and all individuals involved display a complete genome,
with errors in coding, expression, and regulation occurring on chromosomes 1 and 11. The
results of Millar et al, (2000) however, are not widely accepted within the scientific community,
as this abnormality has failed to be recognized in other families displaying multiple cases of
schizophrenia.
The deletion scheme of chromosomal abnormalities has also been shown to influence the
prevalence of schizophrenia. Conclusive studies have indicated a connection between velocardiofacial syndrome, VCFS, and schizophrenia. VCFS occurs due to deletions on chromosome
22q11. Current hypotheses indicate that alterations on chromosome 22q11 may influence ones’
likelihood of developing schizophrenia (Owen & O’Donovan, 2003).
Implications and Future Research
Complex genetic analysis, particularly in the areas of linkage studies, association studies,
and chromosomal abnormalities, has led to the discovery of a variety of potential genetic causes
for schizophrenia. Identification of these suspected causes for genetic disorders can lead
physicians and mental health specialists to more directed and more effective treatment strategies
tailored to the individual and his or her condition. In addition, genetic linkages in schizophrenia
may remove parental guilt associated with a previously held belief that schizophrenia was caused
by childhood upbringing. Yet, a sense of guilt may still exist within parents as they feel that it
was their genes which made their child acquire this devastating disorder.
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In addition, it is imperative to remember that a single, or even fundamental genetic cause
of schizophrenia has yet to be discovered, and furthermore, it is most likely that a single gene or
set of genes will never be proven to be responsible for the devastating horrors of this mental
disorder. Rather, as future research is conducted, additional coding regions will most likely be
identified within affected patients or explored by inquisitive association specialists. These
supplementary findings will increase our current knowledge of the disorder while potentially
offering entirely new perspectives on the subject.
Potential avenues for novel genetic exploration could fill an entire road map. Future
research in the area of linkage studies could possibly include additional study on the remaining
six linkage regions identified by the team of Williams et al., (2003) or further analysis of protein
transcription regions utilizing techniques similar to the study conducted by Enamian et al.,
(2004) in their study of the AKT1 gene. Association studies represent far reaching opportunities
for future study through the identification of entirely new association regions utilizing novel
methods and techniques to carefully analyze the entire human genome. Furthermore,
chromosomal abnormalities are unique to each individual. Study of these abnormalities
represents indefinite possibility for future discovery.
With each of these proposed methods of study, however, it is imperative that one
consider the implications of his or her work. In addition to potential for discovery and the
development of more effective treatments for a severe and devastating mental disorder,
additional research carries with it ethical consequences. If one were to locate a specific marker
for schizophrenia, would individuals have a choice in whether or not they would be tested for the
disease? Who would have access to this information – employers, relatives, children, insurance
companies? What benefit would this knowledge provide for victims?
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Modern society is driven by advances in sciences, in particular, cutting edge genetic and
medical discoveries. As a society, we have the tools to make great strides in identifying and
testing potential genetic linkages, mutations, and associations to schizophrenia and a diverse
array of other mental disorders and physical complications. It is the role of concerned citizens
and motivated scientists to delineate the thin boundary separating the value of scientific research
and exploration with the ethical issues and individual rights of all citizens.
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