Support for association of HSPG2 with tardive dyskinesia in Caucasian populations

Abstract

Tardive dyskinesia (TD) is a severe adverse effect of chronic antipsychotic drug treatment. 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. In the present study, we report a replication study of the five top Japanese TDassociated SNPs in two Caucasian TD samples. Applying logistic regression and controlling for relevant clinical risk factors, we were able to replicate the association of HSPG2 SNP rs2445142 with TD in a prospective study sample of 179 Americans of European origin by performing a secondary analysis of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) genome-wide association study data set, and using a perfect proxy surrogate marker (rs878949; P ¼ 0.039). An association of the 'G' risk allele of HSPG2 SNP rs2445142 with TD was also shown in a sample of Jewish Israeli schizophrenia patients (retrospective, cross-sectional design; P ¼ 0.03). Although the associations were only nominally significant, the findings provide further support for the possible involvement of HSPG2 in susceptibility to TD.

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

“…BDNF is a neuronal growth and survival peptide that modulates a variety of processes including regulation of the dopamine D3 receptor (DRD3) and could thus be involved in TD through this mechanism (75). The heparan sulfate proteoglycan 2 (HSPG2) gene emerged as the top hit in a GWAS of TD screening by Syu et al (115) and was later replicated in a prospective sample by Greenbaum et al (116) but not in a study by Bakker et al (113).…”

Genetics of Common Antipsychotic-Induced Adverse Effects

“…Research has also implicated variants of the SLC18A2 gene and an interaction between SLC18A2 and DRD2 in TD susceptibility [129,140]. Finally, HSPG2 and DPP6 have emerged as promising candidates for the prediction of TD susceptibility [145,146,149]. …”

“…Functional studies of the rs2445142 variant provided further evidence that HSPG2 is involved in TD [145]. Moreover, this association was later replicated by Greenbaum et al [146] in two independent samples, one of Jewish-Israeli ancestry and the other of American-European ancestry. After limiting the control group of the Jewish-Israeli sample to subjects representing an ‘extreme' TD-resistant phenotype, a nominally significant association between the risk rs2445142 G allele and TD was detected.…”

The association between COMT Val158Met gene polymorphism and antipsychotic-induced tardive dyskinesia risk

“…Moreover, a number of investigations found the relationship between functional gene polymorphisms and antipsychotic-induced TD risk. These genes include the DRD2, DRD3, 5-HT 2A receptor, CYP450, GRIN2A, GSTM1, HSPG2, BDNF and SOD2 [6,[9][10][11]34,35]. However, the antipsychotic-induced adverse reaction (such as TD) in most cases probably does not depend on one single factor or on one single gene variant, but rather on many gene variants, gene-gene or gene-environment interactions [28].…”

“…Many studies have indicated some risk factors contributed to TD susceptibility, such as age, female gender, dosage and duration of antipsychotics [5]. Recent candidate gene association studies including genome wide association study (GWAS) have identified suscep-tibility genes for TD, such as dopamine D2 (DRD2), DRD3, 5-HT 2A receptor, GLI2, pyrophosphatase 2 (PPA2), heparan sulfate proteoglycan 2 (HSPG2), dipeptidyl peptidase-like protein (DPP)-6 and brainderived neurotrophic factor (BDNF) [6][7][8][9][10][11]. Additionally, several studies have suggested that the gene-gene interactions contributed to individual variations in TD.…”