Association of the HSPG2 gene with neuroleptic-induced 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.
Syu
Aoi
A
Department of Medical Genetics and Department of Molecular Neurobiology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Ishiguro
Hiroki
H
Inada
Toshiya
T
Horiuchi
Yasue
Y
Tanaka
Syunsuke
S
Ishikawa
Maya
M
Arai
Makoto
M
Itokawa
Masanari
M
Niizato
Kazuhiro
K
Iritani
Shuji
S
Ozaki
Norio
N
Takahashi
Makoto
M
Kakita
Akiyoshi
A
Takahashi
Hitoshi
H
Nawa
Hiroyuki
H
Keino-Masu
Kazuko
K
Arikawa-Hirasawa
Eri
E
Arinami
Tadao
T
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics*; D006801:Humans; D007564:Japan; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010830:Physostigmine / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D012110:Reserpine / Q000009:adverse effects / Q000494:pharmacology; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
D014150:Antipsychotic Agents; D002800:Cholinesterase Inhibitors; D019812:Heparan Sulfate Proteoglycans; C071927:perlecan; D012110:Reserpine; D010830:Physostigmine; D006220:Haloperidol