Association of the HSPG2 Gene with Neuroleptic-Induced Tardive Dyskinesia

作者：Syu Aoi; Ishiguro Hiroki; Inada Toshiya; Horiuchi Yasue; Tanaka Syunsuke; Ishikawa Maya; Arai Makoto; Itokawa Masanari; Niizato Kazuhiro; Iritani Shuji; Ozaki Norio; Takahashi Makoto; Kakita Akiyoshi; Takahashi Hitoshi; Nawa Hiroyuki; Keino Masu Kazuko; Arikawa Hirasawa Eri; Arinami Tadao^*

来源：Neuropsychopharmacology, 2010, 35(5): 1155-1164.

DOI：10.1038/npp.2009.220

• acetylcholine
• neurogenetics
• schizophrenia/antipsychotics
• pharmacogenetics/pharmacogenomics
• tardive dyskinesia

Tardive dyskinesia (TD) is characterized by repetitive, involuntary, and 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 association of a single nucleotide polymorphism, rs2445142, (allelic p = 2 x 10(-5)) in the HSPG2 (heparan sulfate proteoglycan 2, perlecan) gene with TD. The risk allele was significantly associated with higher expression of HSPG2 in postmortem human prefrontal brain (p<0.01). Administration of daily injection of haloperidol (HDL) for 50 weeks significantly reduced Hspg2 expression in mouse brains (p<0.001). Vacuous chewing movements (VCMs) induced by 7-week injection of haloperidol-reserpine were significantly infrequent in adult Hspg2 hetero-knockout mice compared with wild-type littermates (p<0.001). Treatment by the acetylcholinesterase inhibitor, physostigmine, was significantly effective for reduction of VCMs in wild-type mice but not in Hspg2 hetero-knockout mice. These findings suggest that the HSPG2 gene is involved in neuroleptic-induced TD and higher expression of HSPG2, probably even after antipsychotic treatment, and may be associated with TD susceptibility. Neuropsychopharmacology (2010) 35, 1155-1164; doi: 10.1038/npp.2009.220; published online 13 January 2010

• 出版日期2010-4