Role of Genes and Environment in the Aetiology of Schizophre

Role of Genes and Environment in the Aetiology of SchizophreINTRODUCTION schizophrenic disorder (schiz = splitting phrene = mind) is ecumenicly characterized as the fragmentation of psychic operate ons (Bleuler, 1950) of which the absolute ca theatrical roles be unknown. It is defined and diagnosed based on Schneider (1959)s first rank symptoms which locoweed be further categorized into positive (e.g. h each(prenominal)ucination, delusion, etc.) and disallow (e.g. avolition, catatonia, etc.), depending on the set forth and observed experiences of patients (Andreasen Olsen, 1982). This essay aims to review a wide range of scientific literature and interrogation which attempted to airfield the influence of miscellaneous catching and environ intellectual factors in the etiology of schizophrenia based on the general assumption that this mental illness is a multifactorial disease and git be viewed as an outcome of gene-environmental fundamental interaction (Van Os, Rutten , Poulton, 2008). A case study on the execution of Cannabis use on schizophrenia (Caspi et al., 2005) is analysed in order to justify the significance of gene-environment interaction.GENETIC FACTORSThe study of genes and how they contribute to the aetiology of schizophrenia piddle always been the topics of interest for neurobiologist. Multiple touchs studies take away shown that identical twins of 100% shared genes carry almost 40 times higher jeopardize than completely unrelated people in developing such(prenominal)(prenominal) mental disorder if one(a) of them was schizophrenic (Kallman, 1946 Cardno et al., 1999). In fact, schizophrenia is a polygenic illness as no case-by-case significant schizophrenia gene has been identified and numerous candidate genes such as Dystrobrevin-binding protein 1 (dysbindin), neuregulin 1 (NRG1), Catechol-O-methyltransferase protein (COMT), and Disrupted-in Schizophrenia 1 (DISC1) are the aetiological factors (Ross et al., 2006). This ess ay intends to discuss the role of COMT with respect to the dopamine dead reckoning and dysbindin fit to the glutamate supposition.Two neurochemical ideals have evolved to become important theories accounting for the aetiology of schizophrenia. The dominant one is the dopamine hypothesis which pinpointed the association of hyperfunction of dopamine system, critically at D2 receptors, with schizophrenia (Carlsson, 1988) but it is being challenged (Egan et al., 2001) and will be discussed in next section. Another recent simulation will be the glutamate hypofunction hypothesis which suggested that N-methyl-D-aspartate (NMDA) receptors dysfunction and want in glutamate production can lead to negative symptoms of schizophrenia (Olney, 1999 Coyle, 2006).Dopamine hypothesis challenged Introduction of inverted U personate for COMT as the regulator of dopaminergic transmissionCOMT gene, being located at chromosome 22q11.2, is compound in the synthesis of dopamine metabolic enzyme and it regulates the dopaminergic transmission across synapses in the pre head-on cortex (Craddock et al., 2006 Tunbridge et al., 2006). Microdeletion of this chromosomal region resulted in Velo-cardio-facial syndrome (VCFS) and approximately one third of the patients suffering from VCFS were diagnosed to be with schizophrenia (Murphy et al., 1999), depictingthe significance of COMT in aetiology of schizophrenia via regulation of the release of dopamine transmitters in PFC.Two alleles, valine (Val) and methione (Met), establish on COMT are involved in the functional polymorphism which alters the action at law of dopamine metabolic enzyme. The relatively lower stability of the Met allele resulted in the lower enzyme body process, which in turn rock-bottom dopamine breakdown and increase the concentration of dopaminergic transmission in the synapses. Consequently, individuals with Met-Met genotype were expected to be to a greater extent susceptible to schizophrenia (Ross et al., 2006 ). In contrast, research has challenged the dopamine hypothesis by demonstrating that both the patients with schizophrenia and individuals that get two copies of Val alleles (with decreased prefrontal dopamine level) demoed the lowest PFC efficiency (Egan et al., 2001). This leads to the introduction of an inverted U determine (see Figure 1) which illustrates the relationship amidst COMT genotype, PFC dopamine levels and prefrontal activity (Cools DEsposito, 2011).Glutamate hypothesis Dysbindin as the regulator of glutamatergic transmissionDysbindin gene, being located at chromosome 6p22.3, was identified to have strong association with schizophrenia (Straub et al., 2002). There is a wide colocalisation of this gene with dystrobreyin in both presynaptic and postsynaptic regions of whiz such as hippocampus (Benson et al., 2001). The level of dysbindin reflectivity in the hippocampus and prefrontal cortex (PFC) of schizophrenia patients is consistently found to be significantly reduced (Talbot et al. 2004, butterfly et al., 2005 Weickert et al, 2008). As a result of knockdown of endogenous dysbindin protein in nuance by siRNA, a small interfering RNA, glutamatergic neurotransmission can be reduced. (Numakawa et al., 2004 Talbot et al., 2004). Besides, the reduced behavior also significantly suppresses the synaptic transmission of glutamate in drosophilas mind (Shao et al., 2011) and reduces the excitation of NMDA as well as the expression of NR1 mRNA in the PFC of mice (Karlsgodt et al., 2011). These findings well supported the glutamate hypothesis of schizophrenia, which proposed this mental disorder as an outcome of dysfunction of NMDA receptors and glutamatergic transmission.LimitationsAlthough microdeletion of chromosome 22q11.2 increases vulnerability to schizophrenia, it is important to business that there might be other genes on the same lieu that can account for such illness as COMT is not the and gene in this location. Moreover, in contras t to the glutamate hypothesis, reduced dysbindin expression in the hippocampus of mice increases NMDA-mediated current and long-term potentiation and increase glutamatergic transmission (Tang et al., 2009). This suggests that glutamate hypothesis might not be applicable to the role of dysbindin in all pass areas.ENVIRONMENTAL FACTORSStudies using the approach of Magnetic Resonance visualise (MRI) have consistently discovered significant brain deviantities in schizophrenics such as reduced frontal lobes and cerebral cortex (Andreasen et al., 1986) which affected cognitive abilities. Reduced frontal cortex was later shown to have no correlation with familial influence but with environmental factors (Owen et al., 2012). Although Touloupoulou et al. (2010)s study has demonstrate that genetic factors can explain the correlation between cognition and schizophrenia, the research also suggested that environmental factors can account for the weak link between them. This essay will then discuss the influence of antepartum and postnatal risk factors as well as childhood trauma in the aetiology of schizophrenia.Prenatal and postnatal risk factors in aetiology of brain abnormalitiesA meta-analysis has demonstrated the strong correlation between schizophrenia and prenatal or obstetric complications such as below standard blood weight, premature contain and perinatal hypoxic brain damage (Cannon, Jones Murray, 2002). During prenatal stage, deficiency in micronutrients such as folate, iron and vitamin D can go against physical development of fetus and result in low birth weight (Brown Susser, 2008). Maternal exposure to infectious pathogens such as herpes simplex virus type-2, rubella, polio etc. can also bear on neurodevelopment in fetus and raise the vulnerability of offspring towards schizophrenia. Furthermore, hynoxia (deficiency in atomic number 8 level) during perinatal stage significantly influences the development of gray matter which in turn induces sch izophrenia (Opler et al., 2013).Childhood trauma and experiences in aetiology of abnormal functional and structural brain developmentPositive symptoms of schizophrenia such as hallucination is of strong association with undesirable childhood experiences such as maltreat and neglect. Childhood trauma acts as a stressor which adversely alters the dopamine production system in hippocampus. Accordingly, the accumulated effect of abuse can trigger dysregulation of dopaminergic transmission as well as the onset of schizophrenia (Read, Os, Morrison Ross, 2005). The abnormal dopamine level (either too high or too low) is linked with the aetiology of schizophrenia, corresponding to the inverted U model (Cools DEsposito, 2011). In addition, childhood abuse can lead to traumatic brain injury (TBI) which results in neurodegeneration and significant volume loss in various brain regions and eventually leads to the onset of psychosis (Keightley, 2014). 1316GENE-ENVIRONMENT INTERACTIONCase Stud y COMT genotypes moderates the effect of adolescent marihuana-use on risk of schizophrenia in fully grownhood rigid assures have signified the use of cannabis in adolescence as the abject risk factors for schizophrenia. Early use of cannabis is capable of increasing the risk of brain abnormalities and schizophrenia because the brains of adolescents are still under development and brain maturation is extremely susceptible to the deleterious effect cannabis use (Ehrenreich et al 1999 Pistis et al 2004 Pope et al 2003 Schneider and Koch 2003). Nonetheless, this environmental factor simply cannot be regarded as an aetiology of such mental disorder because a vast majority of the cannabis adolescent users do not exhibit schizophrenic disorders in magnanimoushood (Caspi et al., 2005). Hence, the vulnerability of individuals towards adolescent-onset use of cannabis suggests a gene-environment interaction. In fact, COMT gene, as discussed above, is involved in regulating such trait. Ind ividuals who have two copies of Val alleles carry the highest risk of schizophrenia at age 26 if cannabis abuse was found in their early stages, followed by Met-Val genotypes and adolescents who inherited Met-Met COMT genotype are least vulnerable to the abuse use of cannabis (Caspi et al., 2005). Thus, this clearly demonstrates the moderation effect of COMT on cannabis use and the gene-environment interaction. endIn conclusion, understanding the role of various genes such as COMT and dysbindin in regulating the neurotransmission can help developing adequate medications which effectively turnout the mental illness. Identifying the influence of prenatal and obstetric complications as well as childhood experiences in aetiology of schizophrenia can also effectively prevent the onset of schizophrenia. Last but not least, studying the gene-environment interaction in the case of cannabis use reveals the multifactorial properties and intricate aetiology of schizophrenia. Hence, early re search is encouraged to work on such interaction in order to pinpoint the main causes of such mental disorder.REFERENCESAndreasen, N. C., Olsen, S. (1982). negative v positive schizophrenia definition and validation.Archives of General Psychiatry,39(7), 789.Bleuler, E. (1950). Dementia praecox or the group of schizophrenias. Oxford/England International Universities Press. 548.Carlsson, A. (1988). The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology.Cardno AG, marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ, et al. (1999). Heritability estimates for psychotic disorders.Arch Gen Psychiatry,56 (162), 8.Kallmann, F. J. (1946). The genetic theory of schizophrenia an analysis of 691 schizophrenic twin index families.American diary of Psychiatry,103(3), 309-322.Kety, S. S. R. D., Rosenthal, D., Wender, P. H., Schulsinger, F., Jacobsen, B. (1974). Mental illness in the biological and adopted families of adopted individuals who have become schizophrenic A preliminary plow based upon interviews with the relatives.Journal of Psychiatric Research,10(2), 154.Ingraham, L. J., Wender, P. H., Kety, S. S. (1991). Characterization of genetically transmitted schizophrenia in Danish adoptees.Schizophrenia Research,4(3), 279-280.Ross, C. A., Margolis, R. L., Reading, S. A., Pletnikov, M., Coyle, J. T. (2006). Neurobiology of schizophrenia.Neuron,52(1), 139-153.Straub, R. E., Jiang, Y., MacLean, C. J., Ma, Y., Webb, B. T., Myakishev, M. V., Kendler, K. S. (2002). Genetic variation in the 6p22. 3 Gene DTNBP1 the humanity ortholog of the mouse dysbindin gene is associated with schizophrenia.The American Journal of Human Genetics, 71(2), 337-348.Shao, L., Shuai, Y., Wang, J., Feng, S., Lu, B., Li, Z., Zhong, Y. (2011). Schizophrenia skill gene dysbindin regulates glutamatergic and dopaminergic functions via distinctive mechanisms in Drosophila.Proceedings of the National Academy of Sciences,108(46), 18831-18836.Olney, J. W ., Newcomer, J. W., Farber, N. B. (1999). NMDA receptor hypofunction model of schizophrenia.Journal of psychiatric research,33(6), 523-533.Coyle, J. T. (2006). Glutamate and schizophrenia beyond the dopamine hypothesis.Cellular and molecular neurobiology,26(4-6), 363-382.Talbot, K., Eidem, W. L., Tinsley, C. L., Benson, M. A., Thompson, E. W., Smith, R. J., Arnold, S. E. (2004). Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. The Journal of clinical investigation, 113(9), 1353-1363.Weickert, C. S., Rothmond, D. A., Hyde, T. M., Kleinman, J. E., Straub, R. E. (2008). Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophrenia research, 98(1), 105-110.Karlsgodt, K. H., Robleto, K., Trantham-Davidson, H., Jairl, C., Cannon, T. D., Lavin, A., Jentsch, J. D. (2011). Reduced dysbindin expression mediates N-Methyl-D-Aspartate receptor hypofunction and impaired working computer stor age procedure. Biological psychiatry, 69(1), 28-34.Tang, T. T. T., Yang, F., Chen, B. S., Lu, Y., Ji, Y., Roche, K. W., Lu, B. (2009). Dysbindin regulates hippocampal LTP by controlling NMDA receptor step forward expression. Proceedings of the National Academy of Sciences, 106(50), 21395-21400.Egan, M. F., Goldberg, T. E., Kolachana, B. S., Callicott, J. H., Mazzanti, C. M., Straub, R. E., Weinberger, D. R. (2001). Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.Proceedings of the National Academy of Sciences,98(12), 6917-6922.Cools, R., DEsposito, M. (2011). Inverted-UShaped Dopamine actions on human working memory and cognitive control.Biological psychiatry,69(12), e113-e125.Opler, M., Charap, J., Greig, A., Stein, V., Polito, S., Malaspina, D. (2013). Environmental risk factors and schizophrenia.International Journal of Mental Health,42(1), 23-32.Gottesman, I. I., Bertelsen, A. (1989). Confirming unexpressed genotypes for schizop hrenia risks in the offspring of Fischers Danish identical and fraternal discordant twins.Archives of General Psychiatry,46(10), 867-872.Toulopoulou, T., Goldberg, T. E., Mesa, I. R., Picchioni, M., Rijsdijk, F., Stahl, D., Murray, R. M. (2010). Impaired intellect and memory a missing link between genetic risk and schizophrenia?.Archives of general psychiatry,67(9), 905-913.Manoach, D. S. (2003). Prefrontal cortex dysfunction during working memory performance in schizophrenia reconciling discrepant findings.Schizophrenia research,60(2), 285-298.Owens, S. F., Picchioni, M. M., Ettinger, U., McDonald, C., Walshe, M., Schmechtig, A., Toulopoulou, T. (2012). Prefrontal deviations in function but not volume are putative endophenotypes for schizophrenia.Brain, 138.Cannon, M., Jones, P. B., Murray, R. M. (2002). Obstetric complications and schizophrenia historical and meta-analytic review.American Journal of Psychiatry,159(7), 1080-1092.Brown, A.S., Susser, E.S. (2008). Prenatal nutrit ional deficiency and risk of adult schizophrenia. Schizophrenia Bulletin, 34, 10541063Read, J., Os, J. V., Morrison, A. P., Ross, C. A. (2005). Childhood trauma, psychosis and schizophrenia a literature review with abstractive and clinical implications.Acta Psychiatrica Scandinavica,112(5), 330-350.Van Os, J., Rutten, B. P., Poulton, R. (2008). Gene-environment interactions in schizophrenia review of epidemiological findings and future directions. Schizophrenia bulletin,34(6), 1066-1082.Caspi, A., Moffitt, T. E., Cannon, M., McClay, J., Murray, R., Harrington, H., Craig, I. W. (2005). Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene longitudinal evidence of a gene X environment interaction.Biological psychiatry,57(10), 1117-1127.Keightley, M. L., Sinopoli, K. J., Davis, K. D., Mikulis, D. J., Wennberg, R., Tartaglia, M. C., Tator, C. H. (2014). Is there evidence for neurodegenerati ve change following traumatic brain injury in children and offspring? A scoping review.Frontiers in human neuroscience,8.Schneider, K. (1959) Klinische Psychopathologie. New York/Stuttgart Thieme Verlag.