Association of the HSPG2 Gene with Neuroleptic-Induced Tardive Dyskinesia

Abstract

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 ¼ 2 Â 10 À5 ) 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 (po0.01). Administration of daily injection of haloperidol (HDL) for 50 weeks significantly reduced Hspg2 expression in mouse brains (po0.001). 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 (po0.001). 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.

Support for association of HSPG2 with tardive dyskinesia in Caucasian populations

“…In this work, we performed a replication study of the findings of Syu et al 30 in Caucasian populations. We decided a priori to study only the four SNPs for which TD association in the original discovery sample was supported in the validation step, as well as the additional HSPG2 SNP, rs2124368, which survived correction for multiple testing (five SNPs in all).…”

“…31 Although no association was significant after correction for multiple testing, a confirmation step was performed by genotyping the top 63 SNPs in an independent sample of 36 Japanese TD patients and 136 non-TD patients. 30 Four intronic SNPs were nominally associated with TD in both the discovery and confirmation samples: SNP rs2445142 (HSPG2), rs4738269 (KCNB2), rs886292 (ABCC8) and rs2061051 (GABRG3). Focusing on HSPG2, which encodes heparin sulfate proteoglycan 2, an additional 24 tagging SNPs were genotyped in this gene.…”

“…[27][28][29] Although none of the top results reached genome-wide significance, the association of single-nucleotide polymorphism (SNP) rs3943552 in the GLI2 gene with TD was observed in the CATIE sample and independently supported in Jewish Israeli schizophrenia patients of Ashkenazi origin. 29 Syu et al 30 performed a genome-wide association screening of treatment-resistant TD in Japanese schizophrenia patients. In the first step, they studied association of 40 573 tagging SNPs with TD in a small screening sample of 50 TD and 50 non-TD Japanese schizophrenia subjects.…”

“…The risk allele 'G' of rs2445142 was significantly associated with higher expression of HSPG2 in human brain tissue, and Hspg2 heterozygous knockout mice showed lower levels of vacuous chewing movement induced by chronic treatment with a haloperidol-reserpine regiment when compared with wildtype mice. 30 The authors concluded that higher expression of HSPG2 may be associated with increased TD susceptibility.…”

“…In addition to clinical risk factors, TD susceptibility is influenced by genetic predisposition. Recently, Syu et al (2010) reported a genome-wide association screening of TD in Japanese schizophrenia patients. The best result was association of single-nucleotide polymorphism (SNP) rs2445142 in the HSPG2 (heparan sulfate proteoglycan 2) gene with TD.…”