Role of Genes and Environment in the Aetiology of Schizophre

3117 words (12 pages) Essay

11th Apr 2018 Psychology Reference this

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INTRODUCTION

Schizophrenia (schiz = splitting; phrene = mind) is generally characterized as the fragmentation of psychic functions (Bleuler, 1950) of which the absolute causes are unknown. It is defined and diagnosed based on Schneider (1959)’s ‘first rank symptoms’ which can be further categorized into positive (e.g. hallucination, delusion, etc.) and negative (e.g. avolition, catatonia, etc.), depending on the described and observed experiences of patients (Andreasen & Olsen, 1982). This essay aims to review a wide range of scientific literature and research which attempted to study the influence of various genetic and environmental factors in the aetiology of schizophrenia based on the general assumption that this mental illness is a multifactorial disease and can be viewed as an outcome of gene-environmental interaction (Van Os, Rutten, & Poulton, 2008). A case study on the effect of Cannabis use on schizophrenia (Caspi et al., 2005) is analysed in order to justify the significance of gene-environment interaction.

GENETIC FACTORS

The study of genes and how they contribute to the aetiology of schizophrenia have always been the topics of interest for neurobiologist. Multiple twins studies have shown that identical twins of 100% shared genes carry almost 40 times higher risk than completely unrelated people in developing such mental disorder if one of them was schizophrenic (Kallman, 1946; Cardno et al., 1999). In fact, schizophrenia is a polygenic illness as no single 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 essay intends to discuss the role of COMT with respect to the ‘dopamine hypothesis’ and dysbindin corresponding to the ‘glutamate hypothesis’.

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Two neurochemical models 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 model will be the ‘glutamate hypofunction hypothesis’ which suggested that N-methyl-D-aspartate (NMDA) receptors dysfunction and deficiency in glutamate production can lead to negative symptoms of schizophrenia (Olney, 1999; Coyle, 2006).

‘Dopamine hypothesis’ challenged: Introduction of inverted “U” model for COMT as the regulator of dopaminergic transmission

COMT gene, being located at chromosome 22q11.2, is involved in the synthesis of dopamine metabolic enzyme and it regulates the dopaminergic transmission across synapses in the prefrontal 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), found on COMT are involved in the functional polymorphism which alters the activity of dopamine metabolic enzyme. The relatively lower stability of the Met allele resulted in the lower enzyme activity, which in turn reduced dopamine breakdown and increased the concentration of dopaminergic transmission in the synapses. Consequently, individuals with Met-Met genotype were expected to be more 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 inherited two copies of Val alleles (with decreased prefrontal dopamine level) exhibited the lowest PFC efficiency (Egan et al., 2001). This leads to the introduction of an inverted “U” model (see Figure 1) which illustrates the relationship between COMT genotype, PFC dopamine levels and prefrontal activity (Cools & D’Esposito, 2011).

Glutamate hypothesis: Dysbindin as the regulator of glutamatergic transmission

Dysbindin 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 brain such as hippocampus (Benson et al., 2001). The level of dysbindin expression in the hippocampus and prefrontal cortex (PFC) of schizophrenia patients is consistently found to be significantly reduced (Talbot et al. 2004, Bray et al., 2005; Weickert et al, 2008). As a result of knockdown of endogenous dysbindin protein in culture by siRNA, a small interfering RNA, glutamatergic neurotransmission can be reduced. (Numakawa et al., 2004; Talbot et al., 2004). Besides, the reduced expression also significantly suppresses the synaptic transmission of glutamate in Drosophila’s brain (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.

Limitations

Although microdeletion of chromosome 22q11.2 increases vulnerability to schizophrenia, it is important to note that there might be other genes on the same location that can account for such illness as COMT is not the only gene in this location. Moreover, in contrast 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 brain areas.

ENVIRONMENTAL FACTORS

Studies using the approach of Magnetic Resonance Imaging (MRI) have consistently discovered significant brain abnormalities 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 demonstrated 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 prenatal and postnatal risk factors as well as childhood trauma in the aetiology of schizophrenia.

Prenatal and postnatal risk factors in aetiology of brain abnormalities

A meta-analysis has demonstrated the strong correlation between schizophrenia and prenatal or obstetric complications such as below standard birth weight, premature birth and perinatal hypoxic brain damage (Cannon, Jones & Murray, 2002). During prenatal stage, deficiency in micronutrients such as folate, iron and vitamin D can interrupt 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 impact neurodevelopment in fetus and raise the vulnerability of offspring towards schizophrenia. Furthermore, hynoxia (deficiency in oxygen level) during perinatal stage significantly influences the development of gray matter which in turn induces schizophrenia (Opler et al., 2013).

Childhood trauma and experiences in aetiology of abnormal functional and structural brain development

Positive symptoms of schizophrenia such as hallucination is of strong association with undesirable childhood experiences such as abuse 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 & D’Esposito, 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). 1316

GENE-ENVIRONMENT INTERACTION

Case Study: COMT genotypes moderates the effect of adolescent cannabis-use on risk of schizophrenia in adulthood

Strong evidences have signified the use of cannabis in adolescence as the modest 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 alone 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 adulthood (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. Individuals 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.

CONCLUSION

In conclusion, understanding the role of various genes such as COMT and dysbindin in regulating the neurotransmission can help developing adequate medications which effectively tackle 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, future research is encouraged to work on such interaction in order to pinpoint the main causes of such mental disorder.

REFERENCES

Andreasen, 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 Journal 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 adoptive families of adopted individuals who have become schizophrenic: A preliminary report 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 human ortholog of the mouse dysbindin gene is associated with schizophrenia.The American Journal of Human Genetics, 71(2), 337-348.

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Shao, L., Shuai, Y., Wang, J., Feng, S., Lu, B., Li, Z., … & Zhong, Y. (2011). Schizophrenia susceptibility 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 memory performance. 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 surface 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., & D’Esposito, M. (2011). Inverted-U–Shaped 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 schizophrenia: risks in the offspring of Fischer’s 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 nutritional deficiency and risk of adult schizophrenia. Schizophrenia Bulletin, 34, 1054–1063

Read, J., Os, J. V., Morrison, A. P., & Ross, C. A. (2005). Childhood trauma, psychosis and schizophrenia: a literature review with theoretical 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 neurodegenerative change following traumatic brain injury in children and youth? A scoping review.Frontiers in human neuroscience,8.

Schneider, K. (1959) Klinische Psychopathologie. New York/Stuttgart : Thieme Verlag.

INTRODUCTION

Schizophrenia (schiz = splitting; phrene = mind) is generally characterized as the fragmentation of psychic functions (Bleuler, 1950) of which the absolute causes are unknown. It is defined and diagnosed based on Schneider (1959)’s ‘first rank symptoms’ which can be further categorized into positive (e.g. hallucination, delusion, etc.) and negative (e.g. avolition, catatonia, etc.), depending on the described and observed experiences of patients (Andreasen & Olsen, 1982). This essay aims to review a wide range of scientific literature and research which attempted to study the influence of various genetic and environmental factors in the aetiology of schizophrenia based on the general assumption that this mental illness is a multifactorial disease and can be viewed as an outcome of gene-environmental interaction (Van Os, Rutten, & Poulton, 2008). A case study on the effect of Cannabis use on schizophrenia (Caspi et al., 2005) is analysed in order to justify the significance of gene-environment interaction.

GENETIC FACTORS

The study of genes and how they contribute to the aetiology of schizophrenia have always been the topics of interest for neurobiologist. Multiple twins studies have shown that identical twins of 100% shared genes carry almost 40 times higher risk than completely unrelated people in developing such mental disorder if one of them was schizophrenic (Kallman, 1946; Cardno et al., 1999). In fact, schizophrenia is a polygenic illness as no single 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 essay intends to discuss the role of COMT with respect to the ‘dopamine hypothesis’ and dysbindin corresponding to the ‘glutamate hypothesis’.

Two neurochemical models 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 model will be the ‘glutamate hypofunction hypothesis’ which suggested that N-methyl-D-aspartate (NMDA) receptors dysfunction and deficiency in glutamate production can lead to negative symptoms of schizophrenia (Olney, 1999; Coyle, 2006).

‘Dopamine hypothesis’ challenged: Introduction of inverted “U” model for COMT as the regulator of dopaminergic transmission

COMT gene, being located at chromosome 22q11.2, is involved in the synthesis of dopamine metabolic enzyme and it regulates the dopaminergic transmission across synapses in the prefrontal 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), found on COMT are involved in the functional polymorphism which alters the activity of dopamine metabolic enzyme. The relatively lower stability of the Met allele resulted in the lower enzyme activity, which in turn reduced dopamine breakdown and increased the concentration of dopaminergic transmission in the synapses. Consequently, individuals with Met-Met genotype were expected to be more 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 inherited two copies of Val alleles (with decreased prefrontal dopamine level) exhibited the lowest PFC efficiency (Egan et al., 2001). This leads to the introduction of an inverted “U” model (see Figure 1) which illustrates the relationship between COMT genotype, PFC dopamine levels and prefrontal activity (Cools & D’Esposito, 2011).

Glutamate hypothesis: Dysbindin as the regulator of glutamatergic transmission

Dysbindin 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 brain such as hippocampus (Benson et al., 2001). The level of dysbindin expression in the hippocampus and prefrontal cortex (PFC) of schizophrenia patients is consistently found to be significantly reduced (Talbot et al. 2004, Bray et al., 2005; Weickert et al, 2008). As a result of knockdown of endogenous dysbindin protein in culture by siRNA, a small interfering RNA, glutamatergic neurotransmission can be reduced. (Numakawa et al., 2004; Talbot et al., 2004). Besides, the reduced expression also significantly suppresses the synaptic transmission of glutamate in Drosophila’s brain (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.

Limitations

Although microdeletion of chromosome 22q11.2 increases vulnerability to schizophrenia, it is important to note that there might be other genes on the same location that can account for such illness as COMT is not the only gene in this location. Moreover, in contrast 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 brain areas.

ENVIRONMENTAL FACTORS

Studies using the approach of Magnetic Resonance Imaging (MRI) have consistently discovered significant brain abnormalities 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 demonstrated 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 prenatal and postnatal risk factors as well as childhood trauma in the aetiology of schizophrenia.

Prenatal and postnatal risk factors in aetiology of brain abnormalities

A meta-analysis has demonstrated the strong correlation between schizophrenia and prenatal or obstetric complications such as below standard birth weight, premature birth and perinatal hypoxic brain damage (Cannon, Jones & Murray, 2002). During prenatal stage, deficiency in micronutrients such as folate, iron and vitamin D can interrupt 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 impact neurodevelopment in fetus and raise the vulnerability of offspring towards schizophrenia. Furthermore, hynoxia (deficiency in oxygen level) during perinatal stage significantly influences the development of gray matter which in turn induces schizophrenia (Opler et al., 2013).

Childhood trauma and experiences in aetiology of abnormal functional and structural brain development

Positive symptoms of schizophrenia such as hallucination is of strong association with undesirable childhood experiences such as abuse 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 & D’Esposito, 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). 1316

GENE-ENVIRONMENT INTERACTION

Case Study: COMT genotypes moderates the effect of adolescent cannabis-use on risk of schizophrenia in adulthood

Strong evidences have signified the use of cannabis in adolescence as the modest 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 alone 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 adulthood (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. Individuals 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.

CONCLUSION

In conclusion, understanding the role of various genes such as COMT and dysbindin in regulating the neurotransmission can help developing adequate medications which effectively tackle 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, future research is encouraged to work on such interaction in order to pinpoint the main causes of such mental disorder.

REFERENCES

Andreasen, 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 Journal 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 adoptive families of adopted individuals who have become schizophrenic: A preliminary report 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 human 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 susceptibility 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 memory performance. 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 surface 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., & D’Esposito, M. (2011). Inverted-U–Shaped 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 schizophrenia: risks in the offspring of Fischer’s 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 nutritional deficiency and risk of adult schizophrenia. Schizophrenia Bulletin, 34, 1054–1063

Read, J., Os, J. V., Morrison, A. P., & Ross, C. A. (2005). Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications.Acta Psychiatrica Scandinavica,112(5), 330-350.

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