We revealed that the FZD3
gene is significantly associated with the vulnerability to psychosis induced by methamphetamine abuse, and two haplotypes of the FZD3
gene comprising SNP3-4-5-6 (rs2241802-rs2323019-rs352203-rs880481) were identified as potent negative risk factors for methamphetamine psychosis. The G-A-T-G and A-G-C-A haplotypes potently reduce the risks of predisposition to psychosis after methamphetamine abuse to one seventh to one eleventh. In our previous study of schizophrenia [14
], distribution of the SNP2 genotypes and haplotypes comprising SNP2-SNP3 was significantly associated with schizophrenia. Zhang et al. [16
] reported that the haplotype comprising SNP4-SNP5-SNP6 was associated with schizophrenia in a Chinese population. These findings indicate that genetic variants of the FZD3
gene may affect susceptibility to two analogous but distinct psychoses, endogenous psychosis of schizophrenia and substance-induced psychosis. This may imply that Fzd3 is involved in a liability to psychotic symptoms such as hallucination and delusion irrespective of whether they are due to schizophrenia or methamphetamine psychosis.
Dopamine is a key molecule in the pathophysiology of both schizophrenia and methamphetamine psychosis. Enhanced dopamine release in the terminals of mesolimbic dopamine projections was demonstrated in vivo
in patients with schizophrenia, and the amount of the increase in dopamine was positively associated with the emergence or worsening of psychotic symptoms [25
]. Similar phenomena were demonstrated in mesolimbic and mesocortical terminals in animal models of methamphetamine psychosis [23
]. Wnt1 was found to be expressed in close vicinity to developing midbrain dopamine neurons, which are the origins of the mesolimbic and mesocortical dopamine pathways. Wnt1 regulates the genetic network leading to establishment of the midbrain progenitor domain in the ventral midbrain during embryonic development and of the subsequent terminal differentiation of midbrain dopamine neurons [26
]. It is possible that differences in Wnt signaling due to genetic variants of the FZD3
gene affect the development of dopamine neurons of the mesolimbic or mesocortical pathway in early brain development and susceptibility to these two dopamine-related psychoses in adulthood.
Another molecule that potentially links Fzd3 and these two related psychoses is glycogen synthesis kinase-3 (GSK-3), a serine/threonine kinase that is a downstream component of the Wnt/Fzd cascades. Binding of Wnt ligands to Fzd family receptors leads to activation of the intracellular protein disheveled, which inactivates GSK-3β. This in turn leads to the stabilization and accumulation of β-catenin, which translocates to the nucleus where it interacts with nuclear transcription factors for the genes involved in neuronal development. Briefly, GSK-3β mediates Wnt/Fzd signaling cascades. Dysregulation of GSK-3β and 3α is one of promising neurodevelopmental hypotheses of schizophrenia [13
]. GSK-3 is also regulated by dopamine signaling through protein kinase B [29
]. Several studies showed, but not consistently, that GSK-3 protein levels and activities are altered in schizophrenic brains [30
] and lymphocytes [32
]. Several genes, e.g., DISC1
, which have been repeatedly shown to be associated with susceptibility to schizophrenia, are involved in GSK-3/Wnt regulatory pathways [28
]. Recently, the gene encoding DKK4, a component of the GSK-3/Wnt signaling cascade, was shown to be associated with schizophrenia. DKK4 inhibits Wnt-Fzd binding, resulting in inactivation of GSK-3 [34
]. On the other hand, amphetamine also affects GSK-3 activity. Administration of amphetamine to mice increased Ser9 phosphorylation of GSK-3β, resulting in a reduction of its activity in the frontal cortex and striatum [35
], and GSK-3 gene knockdown mice showed a reduced response to amphetamine [36
]. Intriguingly, psychotomimetics of two different classes, phencyclidine and D-lysergic acid, also had the same effects on GSK-3β, which may imply that substance-induced psychosis might be the result of a reduction in GSK-3 signaling. In contrast, chronic treatment with typical and atypical neuroleptics that ameliorate the psychotic symptoms of schizophrenia and methamphetamine psychosis increase the levels and activities of GSK-3 [37
]. It was also found that chronic neuroleptic treatment increased β-catenin in the ventral midbrain, whereas amphetamine decreased it [38
]. These findings indicate that the altered GSK-3/Wnt signaling is involved in liability to expression of positive psychotic symptoms such as the hallucinations and delusions in patients suffering from both schizophrenia and methamphetamine-induced psychosis. This hypothesis may be supported by our present and previous findings because the FZD3
gene was significantly associated with not only schizophrenia but also methamphetamine psychosis.
The present results were still significant even after a Bonferroni correction, although it is possibly a chance finding due to less power. The power analysis showed that our present sample size had more than 80% power to detect a significant difference at 0.05 of any SNP examined, but it must have less power for haplotype analyses. Therefore, our findings should be confirmed in studies using a larger number of subjects and different populations. It may also be useful for further investigation of the roles of Fzd3 in psychoses to examine the genetic association of the FZD3 gene with other types of psychoses, e.g., cocaine-induced paranoia or delusional type of bipolar disorders.