Discuss the role of genes and environment in the aetiology of schizophrenia.

Discuss the role of genes and environment in the aetiology of schizophrenia

Introduction

At the present moment, the aetiology of schizophrenia still remains elusive and replete scientists with more intriguing questions. This severe psychiatric disorder is found to affects around one percent of the human population. Meanwhile, the disorder manifests itself in a wide range of symptoms and peculiar behaviors, such as delusion, cognitive dysfunctions, paranoia, social withdrawal, hallucination and etc. (Pedersen, 2014). Nonetheless, schizophrenia can be characterized in terms of positive and negative symptoms. Positive symptoms can be managed with medication treatment whereas negative symptoms are harder to treat (Sims, 2002). Although researchers are equipped with an amazing array of sophisticated technology, researchers are still in a dearth of definitive answers as schizophrenia does not have a clear cut causes. On the other words, schizophrenia is a highly heterogeneous disease. Nonetheless, scientists are looking into plausible risk factors that could significantly attribute to the development of schizophrenia. Some significant findings have shown the contributions of gene and environment in the aetiology of schizophrenia. Meanwhile, latest studies suggested on the synergistic interplay between genotype and environment in the causality of schizophrenia.

Genetic liability

Based on a genome-wide association study (Purcell et al., 2009), a substantial polygenic variation (involvement of multiple alleles with very small effects) is found to attributes to the risk of schizophrenia. This can occur due to disruptive mutation across many genes, particularly on gene sets that involves the activity-regulated cytoskeleton-associated scaffold protein (ARC) (Purcell et al., 2014). According to Weickert et al. (2004), some schizophrenic patients have significantly reduced expression of dysbindin mRNA as compared to normal population, placing dysbindin as one of the aetiology factors in schizophrenia. It is also found that genetic variation in Neuregulin NRG1 increases individual’s susceptibility to schizophrenia, with elevated type I NRG1 mRNA in schizophrenia (Harrison,& Law, 2006). Meanwhile, other newer study has found the association between NOS1AP gene and schizophrenia, where its gene expression causes excessive protein production in brain (Carrel, 2014). The overabundance of protein affects the development of dendrites and causing abnormalities in brain structure. Nonetheless, according to van Os, Rutten, & Poulton (2008), genes are more likely to affect disorder indirectly through physiological pathways; influences the susceptibility of developing a psychological disorder.

A study by Hirvonen et al. (2005) on genetic vulnerability has found alteration in dopamine system, where the increased in dopamine synaptic availability with increased susceptibility to schizophrenia. An association is found between the higher bindings of D2 receptor in caudate with poorer cognitive tasks performance (involving corticostriatal pathway) that related to schizophrenia risks. For which, this explains the use of dopamine D2 receptor blocking drugs in treating schizophrenic patients. Similarly, findings (Huttunen et al., 2008) have shown high heritability of schizophrenia to first degree relative (FDR). FDR of schizophrenic individuals have statistically higher level of striatal dopamine synthesis as compared to general population.

Nonetheless, despite high heritability and 80% of genetic liability for the illness, no single genetic variation is found to have significant contribution to the development of schizophrenia in individuals (Tandon, Matcheri,& Nasrallah, 2008). Meanwhile, according to Stepniak et al., (2014), their extensive polygenic genome-wide risk association study on schizophrenia has found to be lack of predictive capability when compared to environmental risk factors.

Environmental risks

Cannabis

A recent extensive study of 750 male schizophrenic patients (Stepniak et al., 2014) found that environmental factors are better and more significant predictor of schizophrenia than genetic risk factors. They found that the susceptibility of schizophrenia is proportionate with the increase in number, frequency and intensity of environmental factors. One of which, they identified the avoidable environmental risk such as cannabis use is highly associated with early onset of schizophrenia. Drug abusers who used high potency cannabis on the daily basis are on average having 6 years earlier onset of schizophrenia than non-cannabis users (Di Forti et al., 2014). Meanwhile, researchers found that certain type of cannabis which contains high level of Delta-9-Tetrahydrocannabinol (THC) and no Cannabidiol (CBD), i.e. skunk, has accounted for 32% of schizophrenia cases.

Prenatal environment and early childhood

Research has found obstetric complications (entailing intrauterine hypoxia) as one of the strongest predictor of schizophrenia risk (Walder, Faraone, Glatt, Tsuang,& Seidman, 2014). Similarly, it is found that the maternal exposure to considerable stress (like death of a relative) during the first trimester will increases the susceptibility of the offspring from having schizophrenia in their later life (Khashan et al., 2008).

According to Spauwen, Krabbendam, Lieb, Wittchen and van Os, (2006), the prolonged early childhood traumatic exposure may leads to increase in susceptibility to schizophrenia in adulthood by affecting the functioning of dopamine. It is said that highly stressful traumatic experience causes dopamine hyperactivity in mesocorticolimbic system. Meanwhile, the prolonged exposure to severe stressful trauma promotes the sensitization of dopaminergic system (Tidey,& Miczek, 1996), whereby elevated level of dopamine metabolism is found in sexually abused females (De Bellis et al., 1994). Thus, findings have shown the impact of prenatal and early childhood on neurodevelopment, subsequently attributes to the susceptibility to schizophrenia.

Meanwhile, numerous studies have shown that infection and immune responses are responsible in the aetiology of schizophrenia. Findings reported that children who are exposed to high levels of traffic-caused air pollution (ultrafine concentrated ambient particles- CAPs) during the first year of their life were more likely to develop neurodevelopmental disorders (Allen et al., 2014). Although the study is carried out on mice, the evidence found is promising; as after exposure of the air pollution, elevated levels of glutamate transmitter is observed in mice. Such heightened level of glutamate also observed in schizophrenic patients. The mice which exposed to CAPs had shown significantly larger lateral ventricle when compared to air-exposed mice (Figure 1). Thus, such evidence might explain the causation for the higher reported cases of schizophrenia in the urbanized environment.

Figure 1. The lateral ventricle is larger in the mice exposed to CAPS (right) as compared to air-exposed mice (left) (Allen et al., 2014).

On the other hand, a Danish study has found 45% of individuals who developed schizophrenia had a hospital contact with infection during childhood or adolescence prior to the diagnosis of schizophrenia (Blomström et al., 2014). Although the study could not isolate the types of infections involved, more recent findings by Smith (2014) has found one specific parasite (Toxoplasma gondii) that might have attributed to one-fifth of schizophrenia cases. Such parasite is transmittable through undercooked meat, cat feces and soil.

Interactions between genetics and environment in aetiology of schizophrenia

More exciting findings have motivated researchers to look into the synergistic co-participation between genotype and environment (G x E) in the causality of schizophrenia. Such argued that the effect of one factor dependent on another (van Os, Rutten, & Poulton, 2008). Whereby, environmental factors in schizophrenia might induce DNA methylations that cause the changes in gene expression of neural system (EU-GEI, 2008).  According to Abdolmaleky et al. (2008), they have found potential heritable methylated cytosine residues that could influence the gene expression (of dopaminergic system) that could subsequently affect genetic susceptibility of individuals to certain disorders. Whereas, the hyper- and hypo-DNA methylation could alter the functionality of genes in major psychiatric disorders like schizophrenia. Therefore, the investigation on differential epigenetic alterations which induced by the environmental factors should be made, allowing a more comprehensive understanding towards the aetiology of schizophrenia (EU-GEI, 2008). Meanwhile, Meyer-Lindenberg et al. (2005) has found that catecholamine-O-methyltransferase (COMT) genotype which function as an enzyme that regulate prefrontal dopamine turnover. Presence of such allele can predict on increased of risk for schizophrenia, as it increases dopamine production in the midbrain. The absence of association between cannabis uses with heterozygous COMT valine with methionine alleles and homozygous COMT methionine is found, whereas adolescents with homozygous COMT valine158 allele are more likely to develop schizophrenia if they are exposed to cannabis (Arseneault et al., 2002).

A genome-wide interaction study has found some convincing evidence which shown interaction between single nucleotide polymorphisms and maternal cytomegalovirus that linked to higher risks of developing schizophrenia (Børglum et al., 2014). Whereby, that specific gene was not found to implicate schizophrenia previously, it shown a significant environment-gene interaction. Another 2014 study shown that prenatal health issues and family environmental disruption are significantly greater in genetic high-risk group, thus the evidence supports on the newly proposed ‘polygenic neurodevelopmental diathesis-stress model’ (Walder, Faraone, Glatt, Tsuang,& Seidman, 2014).  Therefore, schizophrenia susceptibility entails both independent and synergistic cofounding biological and environmental factors across development.

 

Conclusion

Recent findings have shed the light on the genetic architecture of schizophrenia, showing the unavoidable heterogeneity of common and rare variants, and de novo mutation in the aetiology of schizophrenia. Therefore, prevalence of schizophrenia can be reduced with evidence-based preventive measures such as reduce or avoid the environmental risk factors. Meanwhile, the discovery of early (genetic) markers for diagnosis of schizophrenia will definitely contributes to the earlier or within the crucial window of opportunity of therapeutic intervention for schizophrenia.

Reference

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