title: DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia.
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.
authors.affiliation: Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: A
authors.initials: A
authors.lastname: Syu
authors.forename: H
authors.initials: H
authors.lastname: Ishiguro
authors.forename: T
authors.initials: T
authors.lastname: Inada
authors.forename: Y
authors.initials: Y
authors.lastname: Horiuchi
authors.forename: M
authors.initials: M
authors.lastname: Ishikawa
authors.forename: M
authors.initials: M
authors.lastname: Koga
authors.forename: E
authors.initials: E
authors.lastname: Noguchi
authors.forename: N
authors.initials: N
authors.lastname: Ozaki
authors.forename: T
authors.initials: T
authors.lastname: Someya
authors.forename: A
authors.initials: A
authors.lastname: Kakita
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Nawa
authors.forename: T
authors.initials: T
authors.lastname: Arinami
mesh_terms: D000483:Alleles; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D044466:Asian People; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics* / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy
chemical_list: D014150:Antipsychotic Agents; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; C503535:DPP6 protein, human; C569992:DPP6 protein, mouse; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases