Evidence of an interaction between
FXR1
GSK3β
Negative Symptoms
Schizophrenia
treatment with antipsychotics
Journal
European psychiatry : the journal of the Association of European Psychiatrists
ISSN: 1778-3585
Titre abrégé: Eur Psychiatry
Pays: England
ID NLM: 9111820
Informations de publication
Date de publication:
19 04 2021
19 04 2021
Historique:
pubmed:
20
4
2021
medline:
20
11
2021
entrez:
19
4
2021
Statut:
epublish
Résumé
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-3β (GSK3β), 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 GSK3β, 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. 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 GSK3β expression. 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. Our findings suggest that, like GSK3β, FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3β pathway for NSs of SCZ.
Sections du résumé
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-3β (GSK3β), 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 GSK3β, 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 GSK3β 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 GSK3β, FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3β pathway for NSs of SCZ.
Identifiants
pubmed: 33866994
doi: 10.1192/j.eurpsy.2021.26
pii: S0924933821000262
pmc: PMC8260562
doi:
Substances chimiques
Antipsychotic Agents
0
FXR1 protein, human
0
RNA-Binding Proteins
0
GSK3B protein, human
EC 2.7.11.1
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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