Comt rs4680 in relation to psychotic experiences

Participants were examined for psychotic experiences at ages 11, 12, 13, 14, 16 using questionnaires and semi-structured interviews. The main sample included 2630 individuals, where 225 individuals responded ‘Yes, definitely’ to any of the 11 psychosis questions at age 16 and 90 of these with reports of using cannabis once or more per month. Participants were examined for cannabis use. The results showed 168 individuals at age 14 with cannabis experience. The individuals that used cannabis at age 14 reported greater psychotic symptoms at age 16 in comparison with those that never used cannabis by this age.

Number of individuals who reported of psychotic experiences was shown in relation to cannabis use and COMT genotype at rs4680 (Table5). The results showed no evidence for an association of COMT genotype and any of the COMT haplotypes with psychosis outcomes (Table 6).

Although the influences of cannabis at age 14 showed an increase in psychotic symptoms among Met/Met carriers, there was also increase in self-reported psychotic experiences among heterozygous (Val/Met) and homozygous for high activity Val allele individuals. Furthermore, there was no evidence that strength of relationship between cannabis and psychosis will be dependent according to the activity of haplotypes.

F

Table 5 The percentage of individuals showing psychotic symptoms as function of cannabis use and COMT variation (Zammit 2011).

indings did not support hypothesis where relationship between cannabis and psychosis is mediated by genetic variation at SNP rs4680. It is possible that examined population did not include participants with same age group or subjects with same psychotic experiences. Cannabis showed to affect individuals differently according to degree of cannabis use during early adulthood (Zammit 2011).

Table 6 Interaction odds ratio (95% CI) between cumulative cannabis use and COMT genotypes on risk of self-reported psychotic experience (Zammit 2011).

Discussion

Most of the studies concerning the use of cannabis as an environmental risk factor to cause psychotic disorders were concentrated with the role of COMT polymorphism as of central importance. The question of whether cannabis acts as independent risk factor for psychotic illnesses or whether it is a proxy to represent genetic factor in the gene and environment interactions (GxE) was presented in the studies of Caspi (2005). Cannabis was considered as environmental risk factor, although there was no main-effect of using cannabis during adolescence on the risk for developing psychosis among carriers of high activity allele (Val/Val). What should also be noted is that adolescent cannabis use found to be associated with later psychosis outcomes, and their link moderated via genetic variation in the COMT gene. Observations of Caspi and colleagues hypothesized the period of adolescence to be one of the sensitive for neurobiological susceptibility to cannabis use. The majority of individuals (92%) showed no signs of psychosis, probably, because adolescent cannabis users had not used cannabis long enough to experience psychotic symptoms. One important issue was discussed that homozygous for Val allele individuals characterized only by one fifth of schizophreniform cases in the cohort. Therefore, this study did not provide evidence for major cause of schizophrenia. What also should be noticed is that psychotic disorders are a product of multiple heterogenous disease processes. Therefore, future work should be focused on the broader phenotype of schizophrenia spectrum psychosis rather than on clinically presented schizophrenia cases. This study provides evidence for Val/Met polymorphism in psychosis only in respect to environmental factors. Therefore, further investigations need to identify the mechanism accounting for GxE interactions. It is possible that reduced dopamine activity in prefrontal cortex in the context with an increase in mesolimbic dopamine transmission by joint effects of adolescent-onset cannabis use and Val/Val genotype results in dysregulation of dopamine therefore leading to psychosis. Other COMT polymorphisms associated with Val158Met polymorphism, which increases the subcortical levels of dopamine, may also interfere with cannabis use. In addition, interaction of COMT polymorphism and cannabis use with other SNPs may increase the risk for psychosis through dysregulation of other neurotransmitters. It was suggested that homozygous for Val allele carriers might be at higher risk for developing psychosis if these individuals were neurobiologically susceptible to illicit lifestyle, oversensitive to threat or predisposed to amplify threat to psychotic levels.

A complex association between the COMT gene and schizophrenia was identified by analysis of seven SNPs distributed in the 27 kb of the COMT gene. What also should be noticed is that SNP rs165688 encoding Val/Met polymorphism was found to exert no effect on schizophrenia risk, which explained previous attempts of investigators to find an association of this SNP with schizophrenia. Because of the high degree of LD between SNPs rs737865 and rs165688, it was suggested that the effect of Val/Met polymorphism on schizophrenia is due to SNP rs737865. The finding which identified SNP rs165599 to affect mainly women and SNP rs737865 to affect both sexes differently showed the possibility of more than one polymorphism at the COMT locus causing an effect for developing schizophrenia among susceptible individuals. Interestingly, studies of Shifman (2002) described SNP rs165688 as most significant evidence for association with schizophrenia and shown to possess different allele distribution for this SNP between men and women. From the data analysed, it was hypothesised that G allele increases risk of schizophrenia in women, but may also reduce female fetal viability. The example of transmission ratio distortion (TRD) in mice identified the influence of sex hormones, which led to the male embryonic lethality and meiotic drive. The finding concerning the presence of sex-specific genetic component to affect schizophrenia relies on the observations, which shown differences in patients with schizophrenia for sex-specific phenotypes in relation to differences in COMT activity. What was noticed is that generally women have 20 to 30% lower COMT activity than men and knockout mice in COMT gene presented sex-specific differences in phenotype. Female patients with schizophrenia and obsessive-compulsive disorder showed the activity of COMT in respect to oestrogen levels in the blood. Most of these mechanisms connect the expression of COMT gene in women with the effects of oestrogen which reduces the activity of COMT enzyme.

Testing 5 SNPs distributed in the region of the COMT gene in the study by J. Costas (2012) helped to find a significant association between low activity gene variants and cannabis use in schizophrenic individuals. This finding provides evidence based on SNPs, haplotypes and genotypes analyses. The results found in the study differed strikingly from the results of Caspi (2005), who found that adolescent cannabis use was linked to later psychosis outcomes among high activity Val allele carriers at rs4680, showing an association of high activity, low activity and gene variants of intermediate activity to be influenced by effects of cannabis. One view is that interaction between cannabis use and genotype in relation to psychosis susceptibility is controlled by several genes in addition to COMT gene. In fact, several gene and gene interactions between COMT and other genes, which regulate neurotransmission, plasticity of synapses and synaptogenesis i n relation to psychosis have been identified. Among them, genes such as GRM3, which affect cortical function and Akt1, which controls signalling pathways (Figure 8). I

Figure 8 Schizophrenia as a genetic disorder of the synapse. Schematic representation of the putative common effect of schizophrenia susceptibility genes on the plasticity and functioning of synapses (Harrison and Weinberg 2004)

dentifying such gene variants and their biological relevance will be helpful in understanding of how the effects of such genes affecting liability to psychosis in the presence of environmental risk factors. One important issue to consider is flip-flop association by which different populations display different frequencies of polymorphisms, therefore presenting different genetic background that might exert different effect for schizophrenia.

Cannabis in itself can induce psychosis indirectly through changes in dopaminergic system or through influencing the cannabinoid system. Cannabis sativa contains different cannabinoids. Most common cannabinoid which has an antagonistic effect on THC is cannabidiol. Through hair analysis, individuals were arranged according to the presence of THC and CBD, THC itself, or none. It was confirmed that THC possesses more positive psychotic-like symptoms than the other two groups. So, it was concluded that if cannabis induced psychosis, its effect would be different among different strains of cannabis with different concentrations of THC and CBD.

The study of Zammit (2007) did not provide evidence for an association of COMT gene and any of the investigated SNPs with cannabis use on the risk of developing psychotic outcomes. Although, it was found that cannabis use in itself may operate as a risk for psychotic experiences. However, given the observed findings from the Dunedin cohort that examined schizophreniform disorder at 26, as a function of cannabis use and variation of COMT gene, found evidence inconsistent to support the hypothesis where link between psychosis and cannabis is moderated by variation at COMT rs4680. Through sensitivity analyses the influences of cannabis use and variation of COMT gene in itself on psychosis showed consistent results, where its interaction effect was modest to increase the risk of psychosis. The results showed that the association of cannabis use with psychotic symptoms did not differ between valine and methionine homozygotes. The negative findings of Zammit and colleagues explain the complex relationship between the COMT genotype, cannabis and schizophrenia.