Evidence of an interaction between FXR1 and GSK3β polymorphisms on levels of Negative Symptoms of Schizophrenia and their response to antipsychotics

Background. Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by glycogen synthase kinase-3 beta (GSK3 beta), which has been implicated in pathophysiology of SCZ and response to antipsychotics (APs). rs496250 and rs12630592, two eQTLs (Expression Quantitative Trait Loci) of FXR1 and GSK3 beta, respectively, interact on emotion stability and amygdala/prefrontal cortex activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NSs) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication. Methods. To test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and FXR1 expression, as already reported for GSK3 beta expression. Results. We found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex. Discussion. Our findings suggest that, like GSK3 beta, FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3 beta pathway for NSs of SCZ.

Automated summary

This study found that the interaction between FXR1 and GSK3 beta genes affects the severity of negative symptoms of schizophrenia and may also impact response to antipsychotic medications. Additionally, chronic olanzapine administration leads to a reduction in FXR1 expression in the mouse frontal cortex.