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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.