Abstract
We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 × 10−6, odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD.
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Acknowledgements
This study was supported by grants from the Mitsubishi Pharma Research Foundation, Kakenhi 23390285, and the Collaborative Research Project (2011-2201) of the Brain Research Institute, Niigata University. Australian human brain tissues were provided by the NSW Tissue Resource Centre, which is supported by The University of Sydney, Neuroscience Institute of Schizophrenia and Allied Disorders, National Institute of Alcohol Abuse and Alcoholism and the NSW Department of Health.
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The authors declare that no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Tanaka, S., Syu, A., Ishiguro, H. et al. DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia. Pharmacogenomics J 13, 27–34 (2013). https://doi.org/10.1038/tpj.2011.36
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DOI: https://doi.org/10.1038/tpj.2011.36
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