







































Abstract: Schizophrenia is often called “the cancer of the brain” because of the lifelong, horrendous implications of 
the disease. Though research has been conducted on schizophrenia for a century or more, it has just recently been 
realized how large a role genetics may play in the development of the disease. This review will discuss why research 
on schizophrenic genes has been difficult, what genes have been found, how the current treatments are being 
revolutionized, and how to progress in this field. The difficulty in research is due in part to the complex genetics 
behind the disease as well as possible environmental factors. The two genes to be discussed in depth, Neuregulin 
1 and SNAP-25, are notable for their complexity. Neuregulin 1 has multiple types of isoforms and genetic variants 
that could lead to schizophrenia and make it difficult to determine where the mutations might be. The SNAP-25 
gene serves multiple purposes in various body and brain regions as an aid to release neurotransmitters, so it can 
be difficult to say which part of the body affected by the gene could lead to a schizophrenia diagnosis. The future 
of schizophrenia research could possibly involve glutamate because of its demonstrated abnormal correlation with 
schizophrenia. Moreover, it’s important that future research focus not only on treating symptoms, but also the patient 
as a whole.

Aisthesis      Volume 10,  201939

A Not-So Beautiful Mind: A Review of the Genetics of 
Schizophrenia 

by Lydia Pack

Introduction 
 Schizophrenia affects approximately one 
percent of the population around the world and 
is often incredibly debilitating (Jia et al., 2010). 
Schizophrenia is over-represented in homeless 
populations, likely because the extreme symptoms of 
the disease can cause people to lose their jobs and 
homes (Fond et al., 2018). Schizophrenic populations 
are largely underdiagnosed, undertreated, and often 
have a multitude of physical and mental illnesses in 
addition to the disease. Since schizophrenia is so 
incapacitating, it makes sense that it is considered 
one of the top twenty causes of disability in the world 
(Leucht et al., 2013). 
 Schizophrenia is a complex disease that is 
typically categorized into two different types: positive 
or negative. The positive type of schizophrenia 
is characterized by symptoms of hallucinations, 
delusions, and disorganized thinking, while the 
negative type is associated with a loss of cognitive 
and social functions (Kay et al., 1987). With recent 
medical advances, negative symptoms are typically 
more difficult to address, as the positive symptoms 
can be treated with antipsychotic medication 
(Kirkpatrick et al., 2006). In a study that followed 

schizophrenic patients for seven years, the patients 
with the least amount of negative symptoms were 
most successful in recovering normal functions 
(Milev et al., 2005). 
 There is no cure for schizophrenia, which is why 
it remains a pertinent issue. There are a number of 
treatment options available, and controversy remains 
over what treatments are most effective. Often, the 
symptoms of schizophrenia are treated instead of 
the condition itself (Harvey et al., 2004). Even if 
medication can be effective, most are expensive, 
have debilitating side effects, and can lead to 
serious effects if discontinued (Leucht et al., 2013). 
Also, improving the symptoms of schizophrenia 
through antipsychotic medication or other types 
of medication does not always, or completely, help 
an individual. Social functioning, the ability to live 
independently, and employment are all challenges 
that schizophrenics face beyond the symptoms of 
their illness (Harvey et al., 2004). 
 Schizophrenic research is ongoing; however, 
from the research already conducted, it seems that 
schizophrenia is based on both environmental and 
genetic factors, but especially genetic. The heritability 
estimates of schizophrenic genes are approximately 



A Not-So Beautiful Mind: A Review of the Genetics of Schizophrenia

Aisthesis      Volume 10,  201940

eighty percent, meaning heritability has been shown 
to have a much greater effect than the environment 
(Jia et al., 2010). Research suggests that a family 
history of schizophrenia can be a significant risk 
factor, but there are also many cases of specific 
gene changes that are risk factors for schizophrenia 
(Yunjung et al., 2011).
 This paper will address the effect of genetics 
on schizophrenia. The first objective will discuss 
why research on schizophrenia has been difficult 
due to the number of possible causal genes and the 
complexity of those genes. The second and third 
objectives will analyze specific genes that may be 
linked to schizophrenia: the Neuregulin 1 gene and 
SNAP-25 gene respectively. The fourth objective will 
look at the current treatments, like antipsychotic 
medication, and discuss future research needs in 
genetics to improve schizophrenia treatments. 
Schizophrenia research has come a long way; 
however, there must be continued research in order 
to better treat not just the symptoms, but the causes.

Objective 1: Difficulties in Research
 While there has been extensive research on 
schizophrenia, there have been multiple roadblocks 
that have prevented progress. The biggest problem 
has been the lack of knowledge about the underlying 
structure and complexity of the genes affected 
(Yunjung et al., 2011). The human genome was only 
mapped out less than twenty years ago, and since 
then, there has been much to learn about how certain 
parts of genes can cause such detrimental effects. 
 There have been multiple types of studies to 
determine possible causes of schizophrenia, one of 
which is karyotyping, a detection of chromosome 
abnormalities through the number and visual 
appearance of chromosomes in a cell’s nucleus. 
Karyotyping showed that a deletion of area 22q11.2 
on a chromosome was a rare but potent risk factor 
for schizophrenia. Similarly, specific copy number 
variations (CNVs)—sections of the genome that are 
repeated—showed this deletion as well as changes 
on areas 15q13.3, 16p11.2, 1q21.1, and NRXN1 on 
the chromosome (Yunjung et al., 2011). Through 
a genomic search for loci that differ between 
schizophrenic patients and non-schizophrenics, 
evidence suggested that schizophrenia was 
polygenic, meaning that genes with too small of a 
phenotypic effect to be observed acted together to 

create a noticeable variation (Yunjung et al., 2011). 
This genomic search also showed that there were no 
common variations of loci to produce a strong enough 
effect. The variety of information from this study 
shows how difficult the genomics of schizophrenia 
are to discern because the possible genetic risk 
factors are often rare or polygenic. Empirical data 
representing a spectrum of risk for specific alleles 
related to schizophrenia are shown in Figure 1, 
which shows that schizophrenic inheritance is based 
on both rare, Mendelian-like genes and polygenes. 

 
 

 
 As aforementioned, the heritability of 
schizophrenia is around eighty percent, which 
means there is still a small portion of causality due to 
environmental factors. However, these environmental 
factors are notorious for being more difficult to 
identify than the biological aspects because of the 
wide range of possible factors, including drug abuse, 
trauma during mother’s pregnancy, nutritional 
factors, prenatal and postnatal development, and 
any other possible trauma, physical or emotional 
(Petronis, 2004). Since the environmental factors 
of schizophrenia and other mental illnesses are 
so elusive, the genomic side has dominated the 
field of research. However, the genomic side is as 
equally complex as the environmental factors; it 
dominates the research side because the genetics can 
be tested experimentally more easily than testing 
traumas (Petronis, 2004). Despite the difficulties 
in researching this complex disease, there has been 
some progress made, as certain genes may play a role 
in the development of the disease.



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Aisthesis      Volume 10,  201941

Objective 2: The Neuregulin 1 Gene
 The Neuregulin 1 gene is known as a schizophrenia 
susceptibility gene and is also incredibly complex. 
The neuregulin genes are a family of four genes 
that play a key part in developmental processes, 
neuroplasticity, and oncogenesis (a process in which 
healthy cells become cancer cells). The Neuregulin 
1 gene, located at chromosome 8p13, [0] has been 
associated with key functions in the heart, breast, and 
nervous system. (Harrison et al., 2003). The gene’s 
structure consists of 1.4 megabases and has more 
than twenty exons as seen in Figure 2. Neuregulin 1 
has six isoforms for one gene (Harrison et al., 2003). 
The differences in promoters can result in differences 
in expression patterns between different isoforms. 
If either exon E68 or E59 are in the gene, there will 
be variants. Exon E68 causes an inclusion of EGFα 
variants, while exon E59 leads to EGFβ variants, 
and the β variants are much more potent than the α 
equivalents (Steinthorsdottir et al., 2004). 

 The Neuregulin 1 protein has been noted for 
binding to receptor tyrosine kinases called ErbB, 
and it has also been noted that any irregularities 
in the pathway of the gene and this receptor has 
been found in schizophrenic patients (Jagannath 
et al., 2018). A study was conducted in mice with 
mutations in Neuregulin 1 and ErbB, and the mice 
with the mutations showed “schizophrenic-like” 
symptoms and were hyperactive (Mei et al., 2008). 
It has also been shown that Neuregulin 1 gene 

polymorphisms can predict schizophrenia patients 
at-risk of psychosis (Jagannath et al., 2018). Both of 
these studies have supported that the Neuregulin 1 
gene is part of the cause of schizophrenia; however, 
it would be difficult to repair this gene because there 
are so many exons and loci on the gene that could 
be responsible for the schizophrenic symptoms. 
Research suggests that most of the genetic variants 
on Neuregulin 1 were either on introns, part of 
synonymous exon substitution, or in a non-coding 
region near the 5’ or 3’ end (Mei et al., 2008). These 
differences are said to cause a change at the level 
of transcription or splicing, and aid in showing the 
complexity of this gene as to how it could cause 
schizophrenia. 
 It is significant to have research on a gene that 
is likely responsible for causing susceptibility to 
schizophrenia. With the information of what genes 
are responsible for creating the incorrect proteins, 
research can continue to determine how this can be 
prevented, or how treatments could overcome the 
effects of the mutations. 

Objective 3: The SNAP-25 Gene
 Another gene that studies have found may 
play a role in causing schizophrenia is the SNAP-
25 gene. This gene is part of a complex that allows 
presynaptic vesicle trafficking, which also means 
the gene helps to release neurotransmitters (Müller 
et al., 2005). In a study of mutant mice without the 
SNAP-25 gene revealed that this gene is essential for 
synaptic transmission, but not for neurotransmitter 
release without a stimulant (Corradini et al., 2009). 
Along with this role, SNAP-25 also interacts with 
different voltage-gated calcium channels. It interacts 
with these channels through a region called synaptic 
protein interaction and controls neuronal calcium 
responsiveness to depolarization through inhibition 
of the calcium channels (Corradini et al., 2009). The 
SNAP-25 gene is also therefore a synaptic protein 
that aids in synaptic vesicle fusion and moderating 
calcium dynamics in response to depolarization, as 
can be seen in Figure 3.
 In schizophrenic patients, there have been 
quantitative differences in the expression of SNAP-
25 in the brain and cerebrospinal fluid (Müller et al., 
2005).  Decreased levels of the gene’s expression were 
found in the hippocampus and frontal lobe within 



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Aisthesis      Volume 10,  201942

schizophrenic patients versus healthy controls. 
Researchers suggested that this decrease coincided 
with the hyperactivity of other parts of the brain 
that are typically associated with schizophrenia 
(Corradini et al., 2009).
 A study conducted on mice with a point mutation 
called blind drunk or Bdr, which is associated with 
the SNAP-25 gene, showed the influence of this gene 
and the environment, specifically prenatal stress, 
on schizophrenia. The study’s results showed that 
sensorimotor deficits that were noted with only the 
point mutation were increased in the presence of 
prenatal stress (Oliver et al., 2009). The results also 
showed that only when the mice had both the point 
mutation and prenatal stress did social interaction 
abnormalities arise within the offspring (Oliver et 
al., 2009). These social interaction abnormalities are 
similar to the social interaction abnormalities that 
can be seen with the negative type of schizophrenia; 
therefore, this study supports that environmental 
prenatal stress and the point mutation can lead 
to schizophrenic symptoms. This study not only 
continues to show the possible effect that the SNAP-
25 gene has on increasing the risk of schizophrenia, 
but also how the genetics and the environment 
could possibly intertwine. While the heritability 
of schizophrenia is high, the environment can also 
contribute either individually or together with 
genetic susceptibility, which raises a whole other set 
of circumstances and obstacles to understanding this 
disease. 

Objective 4: Treatments and Future Research
 While there is still much to be researched 
regarding the genetics of schizophrenia, there are 
treatments now to help address the symptoms of 
the disease. Most of the treatments available for 
the symptoms are antipsychotic medications or 
cognitive behavioral therapy. As stated before in 
the introduction, a majority of the antipsychotic 
medications are too expensive (especially 
considering the large number of schizophrenics who 
are unemployed and homeless), have various side 
effects, and can lead to detrimental effects when the 
medication is discontinued (Leucht et al., 2013). The 
antipsychotics typically reduce dopamine receptor 
function which can help to defray some symptoms, 
but also have dangerous side effects, such as diabetes 
and an increase in blood lipids (Moghaddam, 2004). 
 More recent research has tried to find other 
ways of treating schizophrenics beyond the 
antipsychotics. One study revealed the role of 
glutamate in schizophrenia because multiple 
parts of the body (frontal cortical systems, limbic 
system, basal ganglia, and thalamus) and multiple 
connections (corticocortical, corticolimbic, and 
corticothalamic) that are affected in people with 
schizophrenia are glutamatergic (Moghaddam, 
2004). In addition, there have been reports since the 
mid-twentieth century about an abnormal amount of 
glutamate and an abnormal amount of postmortem 
glutamate receptor binding in schizophrenic patients 
(Moghaddam, 2004). Gated ion channels known 
as NMDA receptors and two ligands—glutamate 
and glycine—are responsible for regulating the 
release of glutamate, glycine, and D-serine through 
presynaptic mechanisms (Moghaddam, 2004). These 
NMDA receptors have been shown to possibly cause 
schizophrenic symptoms if there is any small change 
to the receptor, and factors that could cause these 
changes can be seen in Figure 4. Also shown in the 
figure are the pharmacological sites on the NMDA 
receptor that could be used to treat schizophrenia, 
such as glycine and D-serine binding sites, the 
glycine transporter (Gly T), and the metabotropic 
glutamate (mGlu) receptors (Moghaddam, 2004). 
 Another study showed similar discoveries about 
glutamate and using the findings about glutamate 
for future treatments. This study analyzed seven 
different genes that were said to be linked with 



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Aisthesis      Volume 10,  201943

schizophrenia and found the common theme of 
glutamatergic synapses among all of them (Harrison 
et al., 2003). Figure 5 shows a hypothetical scenario 
in which the seven genes have a shared effect on 
the synapses, which supports  the importance of 
glutamate. By looking into these potential genetic 
sites for intervention, there is hope for more than 
just treating the symptoms, but actually being 
able to treat, or possibly cure, the root cause of 
schizophrenia. 
 There are decades, perhaps even centuries, of 
research done on schizophrenia, but there is only 

a small amount understood about the disease. The 
genes discussed earlier, the Neuregulin 1 and SNAP-
25, are not the only genes to have been linked to 
schizophrenia over the years. Other gene linkages 
to have been reported include dysbindin (a protein 
of a dystrophin-associated complex), Catechol-o-
methyltransferase (one of enzyme that degrades 
catecholamines), the DISC1 (encoding a brain 
protein), RGS4 (Regulator of G-protein Signaling 
4), GRM3 (metabotropic glutamate receptor), and 
the gene G72, which encodes a protein in the brain 
thought to modulate NMDA glutamate receptor 
function as discussed before (Kirov et al., 2006). 
Research suggests that all of these genes have some 
link to the development of schizophrenia. Although 
there is knowledge about these genes, and where 
they are, and what they are doing wrong, there is very 
little knowledge about how to treat them or change 
them (if ethically these treatments were approved). 
 However, even if there were a cure to treat 
the genetic abnormalities that play a large part in 
causing schizophrenia, many schizophrenic patients 
may need help relearning societal expectations. In a 
study of schizophrenic patients who had undergone 
antipsychotic treatment, half of the sample had 
never been married and ninety-five percent of the 
sample had impaired social relationships (Harvey et 
al., 2004). Within the same study, the quality of life 
among schizophrenic patients was found to be low 
even after they had received treatment. Many of the 
patients said that their symptoms of schizophrenia 
were not the reason for their lower quality of life, 
and many cited medication side effects were the 
main culprit (Harvey et al., 2004). The future of 
schizophrenia research will likely involve addressing 
the other issues patients face beyond their generalized 
symptoms.

Conclusion
 From 1955 to 2005, the percentage of Americans 
disabled by mental illness increased fivefold to 
almost six million Americans disabled (Whitaker, 
1970). Schizophrenia is part of this mental illness 
epidemic, as it affects almost one percent of the 
worldwide population (Jia et al., 2010).
 The difficulty in understanding schizophrenia 
is largely due to its complexity. Environmental 
factors have at least a small impact on causing these 
symptoms, and these factors can take the form 



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Aisthesis      Volume 10,  201944

of prenatal chemicals to living emotional trauma 
(Petronis, 2004). The larger complexity though comes 
from genetic factors, but these are not just simple 
Mendelian-like genes. For instance, the Neuregulin 
1 gene can have variant introns, synonymous exon 
substitution, or variants in non-coding regions (Mei 
et al., 2008). Without having just one variant, it 
can be difficult to determine which specific variant 
is causing the abnormality. Another reason for the 
difficulty is that genes like the SNAP-25 gene (where 
it can be seen that there is a correlation between 
schizophrenia and the gene) play a role in so many 
vital parts of the body that it can be difficult to 
understand how exactly SNAP-25 is affecting a 
certain part (Corradini et al., 2009).
 However, the understanding of genes has allowed 
for some progress in the pharmacology of treating 
symptoms of schizophrenia. The recent research in 
how glutamate could play a role in the actual genetics 
aspect of schizophrenia could make a difference in 
one day finding a cure. Future endeavors in research 
for schizophrenia will hopefully either provide a 
solid cure for the root cause in an individual, or more 
likely, will help to treat the individual in a holistic 
way. 
 
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