Research paperThe interaction of GSK3B and FXR1 genotypes may influence the mania and depression dimensions in mood disorders

- GSK3B x FXR1 interactions modulate mania and depression in mood disorder patients.
- This replicates the interaction previously observed in the normal population.
- The interaction was not observed in schizophrenia or on psychosis in mood disorder.
- The risk genotype was associated with a much younger onset (13 years younger).
- Findings can impact early stratification of patients by age of onset or severity.

BackgroundPrevious evidence in healthy subjects suggested that functional polymorphisms GSK3B rs12630592 and FXR1 rs496250 interact in regulating mood and emotional processing. We attempted to replicate this interaction primarily on manic and depressive dimensions in mood disorder patients, and secondarily on schizophrenia patients, diagnosis itself and age of onset.MethodsSymptom dimensions were derived from the Comprehensive Assessment of Symptoms and History 82 items rated lifetime in acute episodes and stabilized interepisode intervals in 384 patients from the Schizophrenia and Bipolar Disorder Eastern Quebec Kindred Study. Linear mixed effect models of symptom dimensions included rs12630592-rs496250 main and interaction fixed effects (obtained from TaqMan genotypes), and a polygenic random effect. The distribution of lifetime best-estimate DSM-IV diagnosis of 855 kindred members was studied versus genotype under a polytomous logistic model.ResultsIn mood disorder patients, the level of mania (in both acute and stabilized periods) and depression in stabilized periods was positively associated with GSK3B rs12630592 T only in FXR1 rs496250 A-allele carriers (Bonferroni-corrected interaction p=0.024, 0.052 and 0.017 respectively). The two polymorphisms explained 11% of mania variance and 5% of interepisode depression variance. The association was observed neither in schizophrenia patients nor with the psychotic dimension in mood disorder patients. Interaction with the diagnosis distribution (p=0.03) was driven by the decreasing prevalence of recurrent major depression with rs12630592 T also only in carriers of rs496250 A.LimitationsSample size was limited, but power was sufficient to detect the tested interaction effect in this replication sample.ConclusionsWe replicate in affective patients an interaction between the FXR1 rs496250 and GSK3B rs12630592 polymorphisms in regulating mood dimensions.