Evidence for association of the GLI2 gene with tardive dyskinesia in patients with chronic schizophrenia

Abstract

Tardive dyskinesia (TD) occurs in approximately 20% of patients exposed to long-term antipsychotic treatment and may be influenced by genetic predisposition, in addition to clinical risk factors. In this study, we implemented a two-step approach to identify susceptibility genes for TD. First, we performed a secondary analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) genome-wide association study (GWAS) dataset to identify candidate genes for TD severity. A total of 327 schizophrenia patients treated with antipsychotics who participated in the CATIE trial were included in a TD severity GWAS (approximately 495,000 SNPs). Cases were defined as demonstrating involuntary movements of a mild degree in two or more body regions or of a moderate to severe degree in at least one body region on at least two separate evaluations, whereas controls were completely free of abnormal involuntary movement on all evaluations. Using logistic regression and controlling for population stratification and relevant clinical risk factors, none of the associated SNPs reached GWAS significance; however, several promising SNPs were identified for follow-up investigation. In the second step, we performed an association study of the top 25 SNPs in an independent sample of 170 Jewish, Israeli, schizophrenia patients (retrospective, cross-sectional design). Association of the SNP rs3943552 T allele in the GLI2 gene with TD was observed in a subsample of Ashkenazi Jewish patients (N = 96, P = 0.018; P = 6.2 × 10⁻⁵ in the CATIE sample). The GLI2 gene encodes a transcription factor that participates in the development of the dopaminergic system during embryogenesis. Taken together, our findings support a possible contribution of GLI2 to TD susceptibility.

Support for association of HSPG2 with tardive dyskinesia in Caucasian populations

“…This sample is essentially the same as reported by us in a previous study, 29 although slightly smaller in terms of participant number (DNAs of four patients were unavailable). Briefly, all 166 participants were Jewish Israeli schizophrenia patients (according to DSM-IV (Diagnostic and Statistical Manual of Mental Disordersfourth edition) criteria), aged418 years.…”

“…To analyze the association of the genotyped SNPs and HSPG2 dyplotypes with TD (two phenotype definitions) in the Jewish Israeli sample, we used logistic regression (additive model). Because of clinical and theoretical considerations (see Introduction), and consistent with our previous study, 29 the following variables were included as covariates: gender, age, years since the inception of antipsychotic treatment and self-reported ancestry (Ashkenazi vs non-Ashkenazi origin). Statistical analysis, including Hardy-Weinberg equilibrium calculation, was performed using PLINK.…”

“…Our original CATIE TD GWAS sample contained 327 patients: 217 of white ancestry (European or Hispanic origin), 102 African Americans and 8 mixed. 29 The analysis was based on phenotypic and genotypic data collected in the CATIE clinical trial and GWAS. 40,41 Of the five SNPs of interest, four were not included in the original CATIE GWAS.…”

“…[21][22][23][24][25][26] Recently, two genomewide association studies (GWASs) and a large candidate gene study of TD were published, based on the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, using two different definitions for TD phenotype. [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.…”

“…[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.…”