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.
Tardive dyskinesia (TD) is the involuntary movement of the tongue, lips, face, trunk and extremities that occurs in patients who are undergoing long-term treatment with antipsychotic medication. TD is often intractable to treatment and the presence of intractable TD is associated with a poorer quality of life.1 Even though recent studies have indicated that most patients have no significant interference in functioning or quality of life from TD,2, 3 identifying patients at high risk for TD is still a high priority for psychiatrists in treatment selection. Second-generation antipsychotics have lowered the risk of TD to approximately 1% annually as compared with the 5% frequency with typical agents,4, 5 although a recent review has reported a much higher annual TD incidence of 3.9% for second-generation antipsychotics as compared with 5.5% for typical agents.6 Furthermore, because second-generation antipsychotics may have few other advantages over older, cheaper drugs, doubt has been raised about the cost-effectiveness of second-generation antipsychotics when based purely on this reduced risk of TD.2 Owing to the lack of effective treatments for TD, its therapeutic management can be problematic for schizophrenia patients receiving antipsychotic medications, especially for those patients who develop severe intractable TD. Therefore, the strategies to prevent TD are often discussed in the context of the safety and use of antipsychotic drugs.7
It is not known why only some patients develop TD, that is, the determinants of its onset are still unclear. At present the etiology of TD may be related to the interaction between the exogenous drugs and the endogenous predisposition, but the nature of TD is so far elusive. In addition to age, gender and ethnicity as suggested risk factors for TD, smoking, drinking and use of street drugs may also increase risk.8 There is some evidence for a genetic component to TD9 and molecular genetic studies of TD were conducted to identify genes related to TD.10
The pathophysiology of TD is not completely understood. In addition to the dopamine super-sensitivity hypothesis of TD,11 there are many other pathophysiological models proposed, including changes in neurotransmitter signaling systems such as γ-aminobutyric acid,12 norepinephrine,13 serotonin14 and acetylcholine,15 which are affected by neuroleptics. In addition to a candidate gene approach,16 two genome-wide association studies (GWASs) based on the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study were published.17, 18 We also reported associations between single-nucleotide polymorphisms (SNPs) on the Illumina Human-1 Genotyping 109K BeadChip and TD in the Japanese sample,19 in which we selected 63 SNPs with allelic P-values <0.002 and located within 10 kb from known genes for subsequent replication analysis, and found three SNPs associated nominally significantly with TD in the replication sample. The allelic P-values in the combined sample were 2 × 10−5 for rs2445142 in HSPG2; 2 × 10−4 for rs4738269 in KCNB2 and 6 × 10−4 for rs2061051 in GBRG3, respectively. We also reported associations of SNPs in the genes grouped into the γ-aminobutyric acid receptor signaling pathway,7 through GWAS by using the Illumina Human-1 BeadChip in a Japanese population. In the present study, we searched for further SNPs associated with TD by using the Illumina HumanHapCNV370 BeadChip to complement our previous results using the Human-1 BeadChip.
Materials and methods
The ethics committee of each institution approved the study. Written informed consent was obtained from all patients after adequate explanation of the study.
The human subjects in this study were 97 Japanese schizophrenia patients with treatment-resistant TD and 199 Japanese schizophrenia patients without TD (Table 1), most of whom have been described elsewhere.7 In brief, subjects were identified at psychiatric hospitals located around the Tokyo and Nagoya areas of Japan. All patients fulfilled the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV20 for schizophrenia. All subjects and their parents were of Japanese descent. All subjects had been receiving antipsychotic therapy for at least 1 year and their TD status was monitored for at least 1 year. TD was assessed according to the Japanese version of the Abnormal Involuntary Movement Scale (AIMS), which was validated by Itoh et al. (1977; in Japanese).21 TD was diagnosed according to the criteria proposed by Schooler and Kane.22 Once TD was identified, the patients were followed up and received standard therapeutic regimens for TD to minimize TD symptoms. If TD persisted after more than 1 year of therapy, patients were considered potential treatment-resistant TD patients. Treatment-resistant TD patients were defined as those patients with dyskinetic movements that persisted more than 1 year and did not improve after at least 1 year of appropriate treatment following guideline-recommended therapeutic regimens for TD. Patients with treatment-resistant TD were all inpatients who had been receiving antipsychotic therapy for controlling both psychosis and persistent severe TD. The treatment options for TD include possible reduction of antipsychotics, as well as switching from conventional antipsychotics to atypical ones, without relapse of their psychotic conditions. The TD status, as well as psychotic conditions, had been checked every 2 weeks for more than 1 year. Based on these observations, the types and the doses of antipsychotic medications were adjusted and determined. We hypothesized that treatment-resistant TD, a severe form of TD, was suitable for detection of genetic association with TD. Only treatment-resistant TD patients were included as those affected with TD in this study. Patients in whom TD never developed despite antipsychotic therapy for more than 10 years were recruited as control patients.
Genotyping and statistics
Association screening was performed by using the Illumina HumanHapCNV370 Chip according to the manufacturer's protocol (Illumina, San Diego, CA, USA). All DNA samples were subjected to rigorous quality control to check for fragmentation and amplification. SNPs on autosomal chromosomes (n=290 527) were extracted. Owing to the small sample size and the fact that gender is not known to have a definite effect on TD, we did not analyze SNPs on the X chromosome. No subjects had genotype call rates <97%. The average genotype call rate was 99.7% and the mean heterozygosity of all SNPs was 30%. Two duplicate pairs of samples were genotyped and showed 99.9% genotype identity. SNPs with more than 5% missing genotypes (n=2853) and those with minor allele frequency <1% (n=28 930) among subjects were excluded. For missing genotypes <5%, SNPs deviating from Hardy–Weinberg equilibrium (P<0.0001; n=1040) were excluded. A total of 257 704 autosomal SNPs passed quality control in the sample.
Replication analysis was performed by genotyping SNPs by the TaqMan method. Allelic discrimination was performed by using the ABI PRISM 7900HT Sequence Detection System, by using the SDS 2.0 software (Applied Biosystems, Foster City, CA, USA). Genotyping using TaqMan probes (Applied Biosystems) was performed twice for each SNP, and genotype concordance was 99.7%. Genotyping completeness was >0.99. We treated those uncalled or discrepant genotypes as missing genotypes. Haplotype blocks in the DPP6 (dipeptidyl peptidase-like protein-6) gene were visualized by using the Haploview program (http://www.broad.mit.edu/mpg/haploview/).
Allelic associations between SNPs and TD, and departure from Hardy–Weinberg equilibrium, were evaluated by χ2-test or Fisher's exact test. Bonferroni's correction for multiple comparisons was applied.
An association was considered significant when the allelic P-value was less than 1.9 × 10−7 in the screening step and allelic P-value (one-tailed) was <0.05 after Bonferroni's correction for the number of SNPs examined in the replication step. The power of our sample (case=61 and control=61) was more than 0.7, with an α of 1.9 × 10−7 assuming a risk allele frequency of 0.3, a disease prevalence of 0.1 and a genotypic relative risk of 4 under the multiplicative model of inheritance, calculated using Genetic Power Calculator (http://pngu.mgh.harvard.edu/~purcell/gpc/). The replication sample had a power of more than 0.7 assuming two SNPs examined and a genotypic relative risk of 2 under the same model in the screening sample.
Human postmortem brains
Brain specimens were obtained from individuals of European (Australian) and Japanese descent. The Australian sample comprised 10 schizophrenic patients and 10 age- and gender-matched controls. The diagnosis of schizophrenia was made according to the DSM-IV criteria (American Psychiatric Association, 1994) by a psychiatrist and a senior psychologist. The control subjects had no known history of psychiatric illness. Tissue blocks were cut from the gray matter in an area of the prefrontal cortex referred to as Brodmann's area-9 (BA9). Japanese samples of BA9 gray matter from Japanese brain specimens comprised six schizophrenic patients and 11 age- and gender-matched controls. Details of the condition of the postmortem brains have been provided elsewhere.23, 24
Analysis of DPP6 transcription in human brain tissue
Total RNA was extracted from human brain tissues by using the ISOGEN Reagent (Nippon Gene Co., Tokyo, Japan). The RNA quality was checked by using a Nanodrop ND-1000 spectrophotometer (LMS, Tokyo, Japan) to yield an optical density (OD) 260/280 ratio of 1.8–2 and an OD 260/230 of 1.8 or greater. The expression of the DPP6 genes was analyzed by using the TaqMan Real-Time PCR system (Applied Biosystems). From RNA, cDNA was synthesized by using ReverTra Ace (Toyobo, Tokyo, Japan) and oligo-dT primers. The expression of the DPP6 gene was analyzed by using an ABI PRISM 7900 HT Sequence Detection System (Applied Biosystems), with TaqMan gene expression assays for DPP6 (Hs00157265_m1) and normalized to the expression of Human GAPDH Control Reagents (Applied Biosystems).
The genotype effects on DPP6 expression were analyzed by analysis of variance followed by post-hoc Student's t-tests by using JMP software version 7.0.1 (SAS Institute, Cary, NC, USA).
To examine the effects of long-term antipsychotic treatments on gene expression, we set up two experimental groups. In the treatment group, 4-week-old C57BL/6J male mice were treated with an intraperitoneal injection of 1.0 mg kg−1 haloperidol (n=10) once each day for 50 weeks. The control group was administered vehicle saline (n=10) under the same regime. The mice were killed 4 h after the last injection to obtain brain tissues. The prefrontal cortex, midbrain, hippocampus, thalamus and striatum were removed by dissection and total RNA was extracted by using an RNeasy kit (Qiagen K.K., Tokyo, Japan). After cDNA synthesis from total RNA samples, the transcription level of cDNA samples was analyzed by TaqMan Expression assay for Dpp6 (Mm00456605_ml; Applied Biosystems) and normalized to that of rodent Gapdh by using Rodent Gapdh Control Reagents (Applied Biosystems). The average relative expression levels in the haloperidol-treated group were compared with the saline groups in each region by analysis of variance.
We tested for allelic association between each SNP and TD by using the χ2-test. The distribution of allelic P-values for association of SNPs with TD is shown in Figure 1a along with Figure 1b showing the quantile–quantile plot. The genomic inflation factor was 1.008. We did not find SNPs at the genome-wide significance level (P<1.9 × 10−7) in the screening sample. Table 2 shows the top 10 SNPs that had an allelic association with TD. The distribution of the genotypes of the 10 SNPs did not deviate from Hardy–Weinberg equilibrium in these SNPs. Three of them were located in the DPP6 gene and two of them were in the SMYD3 gene. The three SNPs in the DPP6 gene were in one linkage disequilibrium (LD) block and the two SNPs in the SMYD3 gene were also in one LD block. Therefore, we selected rs6977820 in the DPP6 and rs2485914 in the SMYD3 genes, which showed the most significant P-values for TD in each LD block, to replicate the association in an independent population. The association between rs6977820 and TD was significant in the replication sample (allelic P-value (one-tailed)=0.008); however, the association between rs2485914 and TD was not significant (allelic P-value (one-tailed)=0.38) (Table 3). The allelic association P-value and odds ratio (95% confidence intervals) between rs6977820 and TD were 4.6 × 10−6 and 2.32 (1.61–3.34) in the combined sample. The distribution of P-values in the DPP6 gene in the screening samples is shown in Figure 2.
The SNP rs6977820 was located within intron-1 and the LD block did not extend to the exons. Therefore, we did not re-sequence the exons of the DPP6 gene. We speculated that the SNP may be associated with the expression levels of DPP6 and, therefore, we conducted real-time PCR for the association between the rs6977820 and the DPP6 expression levels in the human postmortem prefrontal cortex. Analysis of variance revealed a significant main effect of genotype (F(2, 33)=8.1, P=0.001). There was no significant effect of population (Australian or Japanese) (F(1, 35)=2.2, P=0.15) or diagnosis (schizophrenia or control) (F(1, 35)=1.7, P=0.20). Post-hoc analysis demonstrated that the DPP6 levels were significantly lower in the AA genotype than in the GG genotype (P=0.0004) or in the AG genotype (P=0.01). DPP6 levels were highest in subjects with the GG genotype, lowest in the AA genotype and intermediate in those with the AG genotype (Figure 3).
Because TD is caused by long-term use of neuroleptics, we evaluated the effects of long-term administration of haloperidol on the expression of the Dpp6 gene. Significantly higher expression levels of Dpp6 were observed in the prefrontal (F(1, 17)=4.5, P=0.05), striatal (F(1, 17)=6.7, P=0.02), hippocampal (F(1, 17)=7.7, P=0.01) and ventricular midbrain (F(1, 17)=7.9, P=0.01) regions of mice after a 50-week treatment with haloperidol than after a 50-week treatment with saline (Figure 4). We did not observe vacuous chewing movements in mice treated with haloperidol during this study.
The present study identified an allele or risk genotype in the DPP6 gene, which was associated with TD and lower DPP6 expression levels in the prefrontal cortex brain. Long-term administration of haloperidol increased the Dpp6 gene expression in mice. Based on these findings, we hypothesized that long-term administration of neuroleptics increased DPP6 levels in the brain, and that a genetically based reduction in the ability to respond in this way increases the risk for TD.
There have been no reports on the relationship between DPP6 and movement disorders. The deletion at the DPP6 locus has been reported in amyotrophic lateral sclerosis and autism.25, 26 The TD-associated SNP found in this study, rs6977820, is not included in the Affymetrix 500K chip. However, rs4726411, which is in LD with rs6977820 (r2=0.96), is included in the Affymetrix 500K chip (http://www.broadinstitute.org/mpg/snap/ldsearch.php). Two GWASs in the CATIE sample have been published.17, 18 However, an association of the DPP6 gene SNP with TD has not been reported. This may be due to differences in GWAS design, TD definition and/or ethnicity between studies.
In addition to the GWASs in the CATIE sample,17, 18 an association of the SNP rs3943552 in the GLI2 gene with TD was independently supported in Jewish Israeli schizophrenia patients of Ashkenazi origin.18 A large candidate gene study of TD based on CATIE was also reported.27 We were able to evaluate associations in the current Japanese screening sample between TD and 24 SNPs that were among the top results observed in the CATIE sample. Five SNPs were associated with TD with nominal significance and all alleles were in the same direction of risk between the CATIE and Japanese samples (Supplementary Table 1). These findings indicate common SNPs associated with TD beyond ethnicity as well as promising SNPs for further investigation.
In our previous studies, we searched for associations between SNPs on the Illumina Human-1 Genotyping 109K BeadChip and TD.19 We selected 63 SNPs with allelic P-values <0.002 and located within 10 kb from known genes for subsequent replication analysis. One SNP, rs1047053, which is located in the 3′-untranslated region of the DPP6 gene, was included among the top 63 SNPs; however, the association was not replicated. The second most significant association for the SNPs in the DPP6 gene on the Illumina Human-1 Chip was for rs2052218, which is separated from rs6977820 by approximately 14 kb. However, allelic P=0.003 was just outside the criteria for the replication analysis in the previous study. Thus, we did not further examine the association. In this study, we searched for associations by using the HumanHap370 BeadChip. Most of the subjects (100 out of 122) were the same as those studied using the Human-1 BeadChip. However, a small number of SNPs (14 662 SNPs) overlapped and the SNPs of rs2445142, rs4738269 and rs2061051 SNPs were not included in the HumanHap370 BeadChip. The rs1080333 and rs2919415 SNPs on the HumanHap370 BeadChip, which is in LD with rs4738269 in the KCNB2 gene, were able to be analyzed again and showed almost the same allelic P-value with TD (P=0.0005).
The DPP6 gene is preferentially expressed in neurons that contain predominantly Kv4 (hippocampal pyramidal neurons, striatal medium spiny neurons and cerebellar granule cells).28 DPP6 is well known as an auxiliary subunit of the Kv4 channels in CNS neurons, although it may have additional Kv4-unrelated functions in the brain.29 Without DPP6, the Kv4 channels inactivate more slowly and recover more slowly from inactivation than the channels in neurons.30, 31 DPP6 is required to efficiently traffic the Kv4 channels to the plasma membrane and regulate the functional properties of the channels, and may also be important in determining the localization of the channels to specific neuronal compartments, their dynamics and their response to neuromodulators.32 The transient potassium current mediated by Kv4 channels is a common target of dopamine modulation in most cell types.33 Chronic haloperidol treatment upregulates dopamine neuron Kv4.3mRNA and an increased number of functional A-type K+ channels causes a decreased intrinsic firing of dopamine neurons elicited by chronic haloperidol.34 In this study, we observed that expression of Dpp6 was increased by long-term administration of haloperidol. Increased DPP6 may lower the pacemaker frequency of dopamine release, which decreases sensitivity to dopamine. Therefore, we hypothesized that lower levels of DPP6 found in people with the rs6977820 risk genotype may be prone to dopamine super-sensitivity when long-term blockade of the dopamine D2 receptor produces hypersensitivity to dopamine in DRD2.
Several limitations in this study should be mentioned. The biggest weakness is the small sample size. It is difficult to find a large number of subjects who have suffered from treatment-resistant TD. Further replication is necessary. Furthermore, although the identified SNP was associated with the mRNA levels of DPP6, the mechanism for the association has not been clarified. We only analyzed human prefrontal cortex brain and did not analyze mice showing viscous chewing induced by haloperidol only.
The present study implicates DPP6 in susceptibility to TD. However, it does not appear to be the sole genetic determinant. GWAS studies including ours suggest that the genetic nature of susceptibility to TD is multi-factorial inheritance.
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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.
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.
Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website
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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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