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Nyssa Fox
Genetics Paper
November 8, 2007
Genetics of Schizophrenia
Mental illness causes pain and suffering to its victims worldwide. Of the vast range of
mental illnesses, schizophrenia, the disorder most likely to require hospitalization, is one of the
most devastating.1 Afflicting between 0.5 and 1% of the world population, schizophrenia strikes
its victims during their late teens and early twenties, preventing them from continuing a normal
adult life.2 This disease takes a “normal” person and creates a disability that prevents them from
thinking clearly and feeling normal emotions. Some of the most common symptoms include
hallucinations, delusions, disorganized thought and behavior, and blunted emotional affect.1
Unfortunately, though schizophrenia is relatively simple to recognize, the underlying cause still
evades researchers.
Currently, scientists believe that schizophrenia is a neurodevelopmental disorder, arising
from problems in central nervous system development and neural disconnectivity.3 These
malfunctions in connectivity could arise from synaptic abnormalities, high neuron density, or
from myelination and factors affecting it.4 In 2003, David et al. explored possible factors that
could affect neurodevelopment. Though they found that there were “abnormalities in synaptic
protein expression,” the authors were more concerned with the decrease in the overall amount in
white matter in the brains of schizophrenics. Specifically, they found that this decrease in white
matter is likely due to an aberrant development in the myelin of the brain.4 These myelin
changes have been shown to cause psychotic-like symptoms in other diseases, such as
metachromatic leukodystrophy (MLD). Since changes in white matter similar to the changes
that occur in schizophrenia cause psychotic symptoms, Davis et al. concluded that a dysfunction
in myelin maintenance and repair may be a contributing factor to the development of
schizophrenia.
In order to determine if myelin or myelin maintenance is involved in the development of
schizophrenia, researchers first had to determine whether the dysfunction was due to a genetic or
environmental factor. Mental health professionals had noticed that schizophrenia tends to run in
families, but research found that the heritability factor had a large range, between 41-87%.5 To
determine the degree of heritability more accurately, a twin-based study was performed on 106
monozygotic and 118 dizygotic twins with diagnosed psychosis at the Maudsley Hospital in
England.5 Comparison of the concordance rates demonstrated that there was a much higher
concordance for monozygotic twins than for dizygotic twins. These estimates of heritability
ranged between 80 and 87%.5 Though this result did not differ significantly from the previous
results, it did demonstrate that the heritability of schizophrenia was at the high end of the
previous range, indicating that genetics is the primary risk factor for schizophrenia.
Determination of the strong genetic component of schizophrenia and the completion of
the Human Genome Project, pushed researchers to focus on locating a gene or genes responsible
for a predisposition to schizophrenia. They found that microdeletions in chromosome 22q11 can
cause changes in phenotypic expression that include a high frequency of mental illness.6
Furthermore, when researchers looked at the overall frequency of the microdeletion, they found
that it was only present in 0.025% of the entire population. In contrast, it has been identified in
2% of adult schizophrenics and 6% of schizophrenics that developed this disorder in childhood.
Though these rates appear low, they demonstrate that a patient with the 22q11 microdeletion
may have a 20-30 times increased risk of developing schizophrenia.6
Once researchers determined that the 22q11 section of the genome has a relationship to
schizophrenia, they began looking for a specific gene or genes in that section of the genome that
increases susceptibility to the disorder. Since it had previously been demonstrated that a
dysfunction in myelin could lead to psychotic symptoms as well as the overall development of
the disease, Meng et al. chose to look at the RTN4R gene which is located in the 22q11 region.3
This gene codes for the Nogo-66 receptor protein, which binds to Nogo-66 protein, myelin
associated protein, and oligodendrocyte-myelin glycoprotein. When any of these three proteins
bind to the Nogo-66 receptor, they inhibit myelination and axonal growth.3 Therefore, if
demyelination plays a role in the development of schizophrenia, this gene could be actively
involved.
In order to determine if the RTN4R gene is involved in the development of
schizophrenia, Meng et al. looked at 4 single nucleotide polymorphisms (SNPs) in the gene.3
The first three SNPs (rs701421, rs1567871, and rs701427) are located in intron 1, while the
fourth SNP (rs701428) is located in the second intron. A visual layout of the location of the
SNPs is depicted in figure 1.3
Figure 1: Locations of 4 snps in the RTN4R Gene
These SNPs were analyzed in two different ways. First, in a case-control study, 707
people with schizophrenia were compared to 689 control subjects. Genomic DNA was
extracted, and all four SNPs were sequenced. Next, the allele and genotype frequencies were
determined and shown to be in Hardy-Weinberg equilibrium.3 In addition, there were no
significant differences in allele or genotype frequencies between the patients with schizophrenia
and the control group (Table 1).
Table 1: Allele and Genotype Frequencies for the Case-Control Study
A pair-wise disequilibrium test (LD) showed that “all four SNPs were in strong linkage
disequilibrium”3 indicating the recombination rarely occurred between any pair of SNPs. A
transmission disequilibrium test on 372 family trios3 concluded that the four SNP’s are part of a
haplotype block. However, there was no significant difference in the haplotype frequencies
between the patients and the controls.3
Overall, the similarities between allele, genotype, and haplotype frequencies of
schizophrenics and non-schizophrenics suggest that there is no correlation between the RTN4R
gene and schizophrenia.3 However, this does not mean that the RTN4R gene is not involved. It
is possible that this gene only affects some types of schizophrenia so that much larger sample
sizes and comparisons between subtypes would be needed to show the correlation. Alternatively,
RTN4R could interact with other variable genes to induce the disease so that the genetic risk
factors would lie elsewhere in the genome. Therefore, in the future, when analyzing a disorder
as complex as schizophrenia, researchers will have to examine a variety of genes, as well as their
effects on each other. If successful, these efforts could lead to gene therapy or new targets for
drug therapy.
References:
1. Cockerham, W.C. (2006). Sociology of mental disorder (7th ed.). New Jersey
:
Pearson Education, Inc.
2. Andreasen, N.C. & Black, D.W. (2006). Introductory textbook of psychiatry (4th ed.).
Washington DC: American Psychiatric Publishing, Inc.
3. Meng, J. et al. (2007). No association between the genetic polymorphisms in the
RTN4R gene and schizophrenia in the Chinese population. Journal of Neural
Transmission, 114, 249-254.
4. Davis, K. et al. (2003). White matter changes in schizophrenia. General Psychiatry,
60, 443-456.
5. Cordno, A. et al. (1999). Heritability estimates for psychotic disorders. General
Psychiatry, 56, 162-168.
6. Liu, H. et al. (2002). Genetic variation in the 22q11 locus and susceptibility to
schizophrenia. Proceedings of the National Academy of Science, 99, 16859-16864.