Abstract

Tardive dyskinesia (TD) is characterized by repetitive, involuntary, purposeless movements that develop in patients treated with long-term dopaminergic antagonists, usually antipsychotics. By a genome-wide association screening of TD in 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD (non-TD group) and subsequent confirmation in independent samples of 36 treatment-resistant TD and 136 non-TD subjects, we identified an association of SNPs in the HSPG2 (heparan sulfate proteoglycan 2, perlecan) gene with TD. By canonical pathway-based analyses with Ingenuity Pathway Analysis software, we also found that genes involved in the GABA receptor signaling pathway were significantly enriched among the genes with gene-based corrected association allelic P values of less than 0.05. The gene expression levels in the postmortem prefrontal brains in those with the risk genotypes for TD were in the opposite direction to those in mouse brains after long-term admiration of haloperidol. These findings indicate that individuals with the susceptibility to TD may have less ability to adapt to long-term exposure of neuroleptics in some gene expression levels.