Epigenetics Role in Genes Associated With Schizophrenia

Caitlin Harris
California State University, Fullerton

Abstract
Schizophrenia is known as a genetically inherited disease, however the exact mechanisms
have yet to be discovered. Serotonin plays a large roll in schizophrenic symptoms. Methylation
of CpG sites have been shown to cause a decrease in the serotonin receptor expression. In
addition, Hypomethylation of genes other than serotonin receptors have been implicated in the
presence of schizophrenia. There is also a link between epigenetic methylation and siblings with
nuclear parents as well as monozygotic discordant twins affected with schizophrenia. However,
methylation of CpG sites is not the only contributing factor to the diagnosis of schizophrenia.
Methylation to histones has also been implicated in reduced gene expression present in
schizophrenic participants. Considering the results from the above studies, it can be said with
confidence that methylation plays a role in the development of schizophrenia.

Background
It has been widely accepted that schizophrenia is a genetically inherited disease.
However, the mechanisms of how the schizophrenic genes are activated is unknown. Epigenetics
allows alterations in gene expression without changing the genetic code of the DNA. DNA
methylation is one of the greatest contributors to gene expression. Methylation of DNA occurs at
CpG islands and adds a methyl group to the cytosine site of the CpG Island (Carrad, 2011). The
expression of genes can be controlled by the amount of methylation that occurs. The change in
methylation can causes schizophrenic symptoms to emerge. In addition, methylation of histones
can cause post transcriptional changes in DNA (Chase et al, 2013).There are several different
genes that may play a role in the development of schizophrenia. One of the major
neurotransmitters implicated in the development of schizophrenia is serotonin (Carrad, 2015).
However, genes that are not associated with the release and uptake of serotonin have also been
studied. This review will exam the role of epigenetics on the development of schizophrenia.
1. Serotonin Gene regulation
1.1 HTR2A methylation
Schizophrenia is linked with increased levels of serotonin that cause psychosis. The
serotonin receptor type-2(HTR2A) is a target of antipsychotic drugs (Abdolmaleky, 2010). The
level of expression in this gene can be implicated in psychotic symptoms. In brains of
schizophrenic individuals, a decrease in HTR2A expression is common (Abdolmaleky, 2010). In
addition, brain tissue of the frontal lobe of 35 post mortem suicidal schizophrenic individual
showed a large decrease of gene expression. This decrease in gene expression of the HTR2A

gene is caused by hypermethylation of the serotonin receptor (Abdolmaleky, 2010). However,

the CpG site of this receptor is hypo methylated (Abdolmaleky, 2010).
1.2 5HTP1A Methylation
In a study conducted by Carrad et al, blood samples were collected from 40
schizophrenic individuals. The blood was then treated with sodium bi-sulfite to determine the
amount of unmethylated CpG sites of the 5HTP1a gene. The results showed an increase in
methylation levels. Increased methylation levels cause a decrease in the efficiency of the of the
5HTP1A receptor. This would cause an increase in serotonin levels due to the malfunctioning
serotonin receptor. This is consistent with the fact that an increase in serotonin can cause
psychosis. This study was limited by its use of blood samples instead of post mortem brain
samples.
2. Inherited Genetics, Epigenetics, and Schizophrenia
2.1 Nuclear families
Schizophrenia is common in children of those afflicted with schizophrenia. Specifically,
there is a linkage between imprinting of maternal LRRTM1 gene expression and schizophrenia
in offspring (Brucato, 2014). Bisulfate treated DNA showed that methylation of this gene was
decreased in siblings afflicted with schizophrenia. Also, the siblings of schizophrenic parents
showed more similar methylation levels than those who were not related or those who were
related but did not have the active disease (Brucato, 2014). In addition, the DLX5 gene showed a
decreased level of methylation is sibling pairs. DLX5 is a gene associated with the transcription
of LRRTM1. This further links the association between these two genes and the presence of
schizophrenia.

2.2 Twins study

Twins are an ideal subject for the determination of epigenetic factors in the development of
schizophrenia. Although twins share a large amount of identical DNA, their epigenetic codes
may differ. A study conducted by Dempster et al, used whole blood samples from 22 pairs of
discordant monozygotic twins. The CpG site in the promotor of the ST6GALNAC1 gene in
twins afflicted with schizophrenia showed a decrease in methylation. This causes an increased
amount of gene expression. However, in some twins there was a 20% difference in gene
methylation at this site. In addition to twins, post mortem schizophrenic brains were tested for
the same gene methylation. The post mortem brains had a methylation decrease of 25%
compared to unaffected brains. This suggests that a decrease in methylation is associated with
the onset of schizophrenia.
3. Histone Methylation
Histones can alter the genetic expression of DNA by changing the strength of the
chromatin bonds. This change can causes either an increase or decrease in DNA transcription. In
a study conducted by Chase, et al it was found that G9a and GLP are linked to modifications to
H3k9 via methylation (H3K9me). After isolating and testing the DNA from leucocytes of
affected patients, they found an increased amount of G9a and GLP mRNA .This shows an
increase in the activity of H3K9me in patients with schizophrenia. In addition, they found that an
increase in SETDB1 mRNA levels is associated with a worse overall disease prognosis. This
may cause a more chronic and debilitating form of schizophrenia in affected patients. Chromatin
in schizophrenic patients is restrictive and decreases the amount of transcription available in the
genome.

4. Epigenetic effects of drug treatment

A study conducted by Melas et al, used DNA extracted from leukocytes to examine the
levels of DNA methylation in the COMT gene. The experiment showed that DNA
Hypomethylation of the COMT gene was common in patients witch schizophrenia. They then
went on to determine the effects of schizophrenic medications on methylation levels of the gene.
The use of haloperidol was associated with higher methylation levels that were similar to blood
samples from non-affected participants. They concluded that the methylation levels of
schizophrenic patients can be restored by the usage of antipsychotic drugs.
Conclusion
There are many factors that contribute to the presence of schizophrenia. The common
themes in research seems to be that methylation plays an important role in genes that are
correlated with schizophrenia. It was previously thought that epigenetics were specific to an
individual but there is now evidence that epigenetics can be partially inherited. There seems to be
many possible genes responsible for the onset of the disease. The research did not come to a
consensus about a specific gene responsible. This could mean that the genes work together to
initiate the presence of schizophrenia. In addition, there was conflicting information about the
type of methylation that occurs. The genes tested displayed both hypermethylation and
hypomethylation. The only consensus is that epigenetics do play a large part in schizophrenia
and its symptoms. In addition, the identification of these affected genes could help design more
efficient medications to treat schizophrenia.

References
Abdolmaleky, H., Yaqubi, S., Papageorgis, P., Lambert, A., Ozturk, S., et al. (2011). Epigenetic
dysregulation of htr2a in the brain of patients with schizophrenia and bipolar
disorder. Schizophrenia Research, 129(2-3), 183-190.
Brucato, N., DeLisi, L., Fisher, S., & Francks, C. (2014). Hypomethylation of the paternally inherited lrrtm1
promoter linked to schizophrenia. American Journal of Medical Genetics Part B-neuropsychiatric
Genetics, 165(7), 555-563.
Carrard, A., Salzmann, A., Malafosse, A., & Karege, F. (2011). Increased and methylation status of the
serotonin receptor 5htr1a gene promoter in schizophrenia and bipolar disorder. Journal of
Affective Disorders, 132(3), 450-453.
Chase, K., Gavin, D., Guidotti, A., & Sharma, R. (2013). Histone methylation at h3k9: Evidence for a
restrictive epigenome in schizophrenia. Schizophrenia Research, 149(1-3), 15-20.
Dempster, E., Pidsley, R., Schalkwyk, L., Owens, S., Georgiades, A., et al. (2011). Disease-associated
epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar
disorder. Human Molecular Genetics, 20(24), 4786-4796.
Melas, P., Rogdaki, M., Osby, U., Schalling, M., Lavebratt, C., et al. (2012). Epigenetic aberrations in
leukocytes of patients with schizophrenia: Association of global DNA methylation with
antipsychotic drug treatment and disease onset. Faseb Journal, 26(6), 2712-2718.