Genome-wide association study identifies PPP2R2B as a modifier of positive symptom improvement in schizophrenia patients treated with aripiprazole

Schizophrenia is a complex mental disorder with heterogeneous clinical phenotypes. However, the genetic and biological mechanisms behind different symptoms is not clear. The dopamine hypothesis is a widely accepted theory to explain the symptoms of schizophrenia, yet relevant evidence remains incomplete. In this study, we performed a whole genome association in schizophrenia patients treated with 6-week aripiprazole. The result revealed that SNP rs2125443 in PPP2R2B was significantly associated with reduction of positive symptoms on the PANSS scale [ p = 2.89E-08]. PPP2R2B encodes a regulatory subunit of PP2A, and interacts with dopamine receptor D2 (DRD2). The activity of DRD2 is thought to be associated with positive symptoms of schizophrenia, and the gene interaction analysis of PPP2R2B and DRD2 hints that the function of PPP2R2B relies on DRD2. In genotypes with higher DRD2 activity, PPP2R2B showed a more significant differential regulatory effect. Combined with the dopaminergic synaptic signaling, the PP2A/PPP2R2B could serves as mediator in the DRD2–PP2A/PPP2R2B-AKT1 signaling pathway. PPP2R2B may be involved in modulating dopamine signaling during aripiprazole treatment. Our study provides potential evidence supporting how antipsychotic drugs modulate dopamine activity at a fine regulatory level, and identifies PPP2R2B as key mediator in the downstream signaling cascade. Our findings support a genetic association between PPP2R2B and positive symptom improvement in schizophrenia patients receiving aripiprazole treatment. Clinical trial registration number ChiCTR1800014755.