The Genetic Linkage to Schizophrenia - Essay Example

Is there a hereditary/genetic linkage to Schizophrenia? of the Under the guidance of APA format Is there ahereditary/genetic linkage to Schizophrenia? Schizophrenia, which is commonly known as madness, is a chronic psychotic disorder of thinking, behavior and perception. The disease is actually not yet well understood in terms of etiology and pathogenesis. The course of the disease is usually fluctuating. It either gradually deteriorates or is relatively stable. The disease can be mild and subtle wherein the individual adapts very well to everyday life or can be severe with full expression of symptoms. These symptoms can be either positive or negative. The hallmark symptoms are auditory hallucinations and delusions. Schizophrenia is now considered a broad syndrome expressed by various brain disorders. Though it yet unclear as to what causes schizophrenia, some research has pointed to the role of changes in neuroanatomy, neurochemistry and neurodevelopment either due to environmental interactions or due to genetic mecahnisms, in the pathogenesis of schizophrenia. Of recent interest is the genetic or hereditary link in the development of schizophrenia. It is now clear that in those who develop schizophrenia with heritability attributes, the major determinant is genetic predisposition in 80 percent of the cases. Some candidate genes, polymorphisms and linkage regions like val158met, dopamine metabolizing gene COMT polymorphism and MAOA, DAT1, SLC6A4 variants have been reported to be possibly associated with schizophrenia but with no clear demonstration of association. However, no candidate genes or polymorphisms are clearly well understood. Thus recent research has placed schizophrenia under the category of heritable diseases without any definite genetic abnormality being identified. In this essay, genetic link to schizophrenia will be explored through review and critical analysis of pertaining literature. Critical analysis Need, Ge, Weale et al (2009) investigated single nucleotide polymorphisms (SNPs) using a significant number of patients and controls by following the top hits in four independent cohorts of European origin. The researchers did not find significant genome-wide associations notr did they find any evidence to support previously reported genome wide associations or candidate genes. Further on, the researchers examined copy number variants or CNVs by using a subset of significant number of cases and controls of European ancestry and of African ancestry. In this evaluation, it was found that 8 cases of schizophrenia had deletions of greater than 2 mb which was significantly absent in the controls. The deletions identified were at 8p22 and 16p13.11-p12.4. Other deletions which were reported by scientists previously were also found to be associated with schizophrenia in this study. They are NRXN1 and APBA2. The authors concluded that though minor CNVs are associated with the development of schizophrenia, it is yet unclear as to whether, large and rare CNVs can be implicated in the predisposition of schizophrenia. What may be predispose to schizophrenia is recurrent mutation of specific genomic regions in schizophrenia. In this study by Need et al (2009), which is the largest whole genome association studies pertaining to schizophrenia, though the authors conducted a wide genome scan, they could not find any definitive association between SNPs and increased risk of schizophrenia. Of the SNPs scanned, ADAMTSL3 gene had the strongest association with schizophrenia. This study indicates the need for recruitment of larger number of SNPs and implausible genetic model to ascertain the association between SNPs and heritability of schizophrenia. According to van Os, Rutten and Poulton (2008), gene-environment interactions are the predisposing factors for the development of schizophrenia and can be categorized into ecogenetics, genetic moderation of sensitivity of environment, environmental impact on methylation and DNA sequence and gene-environment correlation. According to ecogenetic principles, genes influence the psychiatric disorder through indirect mechanisms through their impact on the physiological pathways and thus either increase or decrease the likelihood of developing psychiatric disorder, but not directly cause the disorder. Thus, it has been thought that biological synergism plays a major role in the development of psychoses like schizophrenia. Another concept that has been thought of pertaining to genetic linkage to schizophrenia is the genetic moderation of sensitivity of the environment. Thus, genetic endowment differences make different individuals in the same environment respond differently. Environmental factors can also have impact on the sequencing of the DNA by causing de novo mutations by methylation of DNA or by altered gene expression through mutations. The second mechanism, an epigenetic mechanism is in early stages of research and is not yet well established. According to the principles of gene-environment correlation, gene-environment correlation can cause schizophrenia and explains how differences in individuals genotype and cause a drive in the differential environmental exposure. Gilks, Allott, Donohoe et al (2009) conducted a search for functionally relevant genes with evidence of linkage to schizophrenia. Using multi-stage association design, the researchers selected HOMER-2 as the candidate gene for schizophrenia. For this purpose, they genotyped 26 tagging SNPs from cases and controls in Ireland. Also, secondary replication analysis was performed by using European Consortium samples and controls. The researchers found that SNP of protective allele rs2306428 was significantly associated with schizophrenia. This was because the allele removes a splice enhancer binding site which has been predicted for schizophrenia and where HOMER 2 is naturally truncated. The researchers did not find any effect on the HOMER splicing by allelic effect of rs2306428. Thus, it is clear from the study that HOMER 2 can be implicated in the susceptibility of schizophrenia. The authors concluded that more research is warranted to elucidate the role of HOMER 2 gene in the predisposition of schizophrenia. Conclusion From the above studies it is clear that genetic linkage to schizophrenia is possible. So far there have been no candidate genes identified for the susceptibility of schizophrenia. HOMER 2 is a possible candidate gene, but requires further study and research. Some SNPs and CNVs, may have possible role in the hereditary transmission of the disease as evident in some European cases, but even this is not clear and warrants further research. In most cases, the result of the disease is most probably due to various gene-environment interactions and not the gene alone. Genes make the individual susceptible to environmental factors or the environmental attributes alter the genetic components and such interactions have been implicated in the pathogenesis of schizophrenia. As of now, genetic linkage to schizophrenia is only a proposal which needs further research. References Gilks, W.P., Allott, E.H., Donohoe, G.,E. et al. (2009). Replicated genetic evidence supports a role for HOMER2 in schizophrenia. Neurosci Lett.,. [Epub ahead of print] Need, A.C., Ge, D., Weale, M.E., et al (2009). A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia. PLoS Genet., 5(2): e1000373. Retrieved on 1st December, 2009 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631150/?tool=pubmed van Os, J., Rutten, B.P.F., and Poulton, R. (2008). Gene-Environment Interactions in Schizophrenia: Review of Epidemiological Findings and Future Directions. Schizophr Bull., 34(6): 1066–1082. Retrieved on 1st December, 2009 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632485/?tool=pubmed Read More