Gene variations of cnr1 and cnr2 in neuropsychiatric disorders
The ubiquitous cannabinoid receptors were found to be the most abundant binding sites in the central nervous system and therefore known to have an association with neuropsychiatric disturbances. A number of natural polymorphisms in cannabinoid receptor genes have been described to be associated with human disorders such as osteoporosis, drug dependency, depression and schizophrenia in the diverse ethnic groups, including European-American, African-American, Japanese subjects. Most commonly, the relationship between neuropsychiatric disorders and variation in cannabinoid receptor genes involved other genetic variations. The information about gene variants, which were generated by post-transcriptional and post-translational modifications, would help to identify if these variants influence the behavioural and physiological effects of cannabis use (Onaivi 2013). Therefore investigations of pharmacological diversity of the cannabinoid receptors would help to target receptor conformations and detect their pharmacological responses.
GxE interactions
Combined interaction of individual genes and environmental factors with other genes and other environmental factors results in the change of phenotype (Tsuang 2004). Complex disorders such as schizophrenia come from range of genetic and environmental factors and its interaction (GxE interactions). One of the environmental factors that could interfere with genes is cannabis. Pharmacological studies have shown that administration of psychoactive ingredient of cannabis THC results in the events of transient positive and negative effects as well as cognitive deficits both in healthy and in schizophrenic individuals. The prevalence of cannabis use is much higher in individuals with psychotic disorders than in the general population. It is not understood whether cannabis causes psychosis or may be a consequence of it, but it is reasonable to expect that the effects of using cannabis on risk of psychosis will be different from individual to individual in relation to other risk factors that may be associated with the illness. Even if cannabis use increases the risk of schizophrenia disorder, it will not be enough for itself to produce the disease. Nevertheless, available evidence indicates that cannabis use during period of adolescence and young adulthood increases the risk for psychotic disorder later in life (Veling 2008).
Comt polymorphism is a mediator of the link between cannabis and psychosis.
One attractive gene to examine the gene and environment interaction is catechol-o-methyltransferase. COMT is a good candidate for study because it is located on the 22nd chromosome in the region showed to be involved in the genome scans of schizophrenia. Moreover, a microdeletion of chromosome 22 was shown to be associated with velocardio-facial syndrome, characterised by high rates of psychosis (Caspi 2005). Studies reported 20 - 30% of all patients with velocardio-facial syndrome were diagnosed with schizophrenia-like symptoms. Therefore, 22q11 deletion is known as major component cause for schizophrenia (Ohi, 2013). The enzyme encoding COMT gene is involved in the catabolism of cathecholamine neurotransmitters such as dopamine, epinephrine and norepinephrine.
S
Figure 2 Genomic structure of the COMT gene, which shows exon position of the membrane-bound (MB-COMT) and soluble (S-COMT) forms and location of SNPs (Bray 2003).
ingle
nucleotide polymorphism (SNP) of the COMT gene results in a guanine
to adenine missense mutation that substitute a valine (Val) to
methionine (Met) at codon 158 ( Val158Met), generating decrease in
enzymatic activity and decrease in breakdown of dopamine. Carriers of
the Met/Met genotype have the lowest enzymatic activity, whereas
carriers of Val/Val genotype have the highest, heterozygotes Val/Met
of rs4680 appear to be of intermediate activity because of the two
codominant alleles (Shifman 2002). Functional COMT protein exists as
a soluble COMT form (S-COMT) in cell cytoplasm and as membrane-bound
COMT (MB-COMT), which is most prevalent in the brain (Figure 2).
The transmembrane form of COMT is generally involved in deactivation of neurotransmitters in the pre- and postsynaptic neurons, whereas COMT soluble isoform generally found outside the central nervous system in cells, such as monocytes, mammary and intestinal epithelium and believed to operate toxic catechols.
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Figure 3 Relationship between efficiency of cortical function (y axis) and cortical dopamine concentration (x axis), as a function of COMT polymorphism. In patients the highest cortical function efficiency is associated with Met/Met genotype. Thus, in healthy subjects good efficiency of cortical function is associated with Val/Val genotype. So, variation in COMT gene and dopamine availability will have the opposite effect on efficiency of cortical function among patients and healthy subjects (Diana P.Prata 2009).
he efficiency of cortical function was shown to be mediated by variation in the COMT gene, which controls dopamine levels in the brain (Figure 3). Healthy and schizophrenic individuals were examined for the effect of the COMT genotype variation on cortical function. Neuroimaging analysis has shown differences in cortical function during task performance.
Schizophrenic patients have shown greater cortical activation than controls, as function of impaired cognitive work efficiency and decreased dopaminergic enzyme activity (Diana P.Prata 2009)
The COMT polymorphism has been extensively studied as risk factor for psychosis in the context of exposure to the environmental pathogens. Although individually cannabis and COMT gene have collected not enough evidence to cause psychotic disorders but it was suggested that their joint effect may be stronger, because both appeared to affect cognitive and physiologic functions that are implicated in genomes scans of schizophrenia (Caspi 2005).
Aims
The aim is to determine whether genetic variation in the COMT moderates THC-induced effects on psychotic symptoms among patients with schizophrenia and healthy individuals. Several other SNPs and haplotypes across the COMT gene are tested in order to better characterise functional variants that might be involved in susceptibility to schizophrenia.