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Analysis of genetic variations in the human Par-4 (PAWR) gene and tardive dyskinesia in schizophrenia.

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Neuropsychiatric Genetics
Analysis of Genetic Variations in the Human Par-4
(PAWR) Gene and Tardive Dyskinesia in Schizophrenia
Ying-Jay Liou,1,2 Mao-Liang Chen,3 Ying-Chieh Wang,3,4 Jen-Yeu Chen,3 Ding-Lieh Liao,5 Ya-Mei Bai,1
Chao-Cheng Lin,6 Tzu-Ting Chen,3 Geng-Han Mo,3 and I-Ching Lai3,4*
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
Yuli Mental Health Research Center, Department of Psychiatry, Yuli Veterans Hospital, Yuli, Hualien, Taiwan
Institute of Medical Science, Tzu Chi University, Hualien, Taiwan
Department of Psychiatry, Pali-Psychiatric Hospital, Taipei, Taiwan
Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
Received 9 January 2008; Accepted 28 April 2008
Tardive dyskinesia (TD), a persistent and irreversible movement
disorder, usually develops after long-term antipsychotic treatment.
TD is thought to be a complex trait, so it is highly suspected that
there are several genes simultaneously involved in the pathogenesis
of TD. Because all typical antipsychotics are blockers to the dopamine D2 receptor (DRD2), researchers have reported several
genetic variations in the human DRD2 gene relating to
antipsychotic-induced TD [Liou et al., 2006; Zai et al., 2006,
2007; Mo et al., 2007]. Recently, prostate apoptosis response 4
(Par-4), a leucine zipper containing protein, was identified as a
regulatory component of DRD2 signaling. Par-4 is expressed in
various brain regions, including the medium spiny neurons of the
striatum, where most dopaminergic inputs are processed. Par-4
specifically interacts with DRD2 via its leucine domain, and it can be
coimmunoprecipitated with DRD2 in mouse brain lysate. Once
DRD2 is activated, Par-4/DRD2 complex formation is necessary in
the maintenance of inhibitory tone in dopamine-mediated cAMP
signaling. Disruption of the complex formation may facilitate
calmodulin/DRD2 complex formation upon Caþþ influx and
subsequently up-regulate dopamine–cAMP–CREB signaling
[Park et al., 2005]. Collectively, the evidence suggests Par-4 to be
an abstractive candidate for study of its relationship with TD. Par-4
is encoded in the gene of PRKC apoptosis WT1 regulator protein
(PAWR), which is located in chromosome 12q21 and consists of 7
exons. In the present study, we hypothesized that genetic variations
of the PAWR gene might be related to susceptibility to TD and tested
this hypothesis.
All recruited schizophrenic inpatients were: diagnosed by two
senior board-certificated psychiatrists according to the criteria of
DSM-IV, treated with typical antipsychotics persistently in the past
2 years, maintained on a stable dosage of antipsychotic agent for
6 months before the clinical assessment of TD, and Han Chinese.
Patients with the following criteria were excluded: aged over 65 or
under 18 years, organic mental disorder, history of mood disorder,
Ó 2008 Wiley-Liss, Inc.
How to Cite this Article:
Liou Y-J, Chen M-L, Wang Y-C, Chen J-Y,
Liao D-L, Bai Y-M, Lin C-C, Chen T-T, Mo
G-H, Lai I-C. 2009. Analysis of Genetic
Variations in the Human Par-4 (PAWR) Gene
and Tardive Dyskinesia in Schizophrenia.
Am J Med Genet Part B 150B:439–440.
neurological illness, diabetes mellitus, history of substance use
(alcohol, amphetamines, and opioids) and history of atypical or
second-generation antipsychotic treatment. This study was approved by the Yuli Veterans Hospital Institutional Review Board
in advance, and informed consents were obtained from all enrolled
patients. The senior psychiatrists (Dr. Lai IC, Dr. Bai YM, Dr. Lin
CC, Dr. Liao DL, and Dr. Chen JY) were experienced in using the
Abnormal Involuntary Movement Scale and were blind to the
genotypes of patients. TD was defined according to the Research
and Diagnostic Criteria for persistent TD [Schooler and Kane,
1982]. For confirmation of diagnoses of TD, all patients were rated
again about three months later. Non-TD was defined as the absence
of any abnormal involuntary movements in the two successive
We selected genotyped genetic markers in a combined CHB and
JPT population from the International HapMap Project (http:// Ninety single nucleotide polymorphisms
*Correspondence to:
Dr. I-Ching Lai, Department of Psychiatry, Yuli Veterans Hospital,
Hualien, Taiwan. No. 91, Shin-Shin St., Yuli, Hualien 981, Taiwan.
Published online 27 May 2008 in Wiley InterScience
DOI 10.1002/ajmg.b.30795
TABLE I. Haplotype Analyses of the PAWR Gene in the TD and
Non-TD Groups
TD, %
Non-TD, %
Generated after 100,000 permutation tests.
(SNPs) were obtained, of which 41 had minor allele frequencies
greater than 10%. Among these 41 SNPs, five were selected to be
block-tagging SNPs (tSNPs), because they fully represented haplotypic variation greater than 5% using the Gabriel algorithm. The
five SNPs studied here (rs1705769, rs7305141, rs8176874,
rs7955388, and rs2307220) ranged over 69.3 kb in distance, covering 70% of the full length of the PAWR gene, so we genotyped the
five SNPs of each enrolled patient.
Finally, 398 schizophrenic inpatients were enrolled (TD ¼ 246,
non-TD ¼ 152), and there was no significant difference between the
groups’ demographic and clinical information, such as gender and
smoker distribution, mean age, years of antipsychotic exposure and
chlorpromazine equivalent dosages. Every selected tSNPs was
distributed in the Hardy–Weinberg Equilibrium. Neither the genotype nor the allele distribution of the SNPs showed a significant
difference in frequency between the TD and non-TD groups.
Inter-marker linkage information was evaluated first and the five
SNPs are proved in a haplotype block. Haplotype analyses failed to
show any significant association between the haplotypes of PAWR
gene and TD, either in every single haplotype or in the global
analyses (P > 0.1 for all permutations; Table I).
Based on the results above, we were unable to show any association between genetic variations in the human PAWR gene and the
susceptibility of TD in schizophrenic patients. There are several
possible interpretations of our findings: first, there are several
downstream signaling regulators for DRD2 neurotransmission,
and other signaling molecules might play a more dominant role
than Par-4 in the pathogenesis of TD. For example, Kovoor et al.
[2005] recently demonstrated that RGS9 knock-out mice develop
involuntary movements resembling a drug-induced dyskinesia
model when inhibition of dopaminergic transmission is followed
by activation of D2-like dopamine receptors. It would therefore be
interesting to study whether genetic variations in the human RGS9
gene are associated with TD susceptibility. Although a recent study
reported no significant association between several variants of the
RGS9 gene and antipsychotics-induced extrapyramidal symptoms,
the effects of these variants on long-term adverse effects related to
antipsychotics, such as TD, remain to be explored, as the study
focused on acute movement adverse effects after only 2 weeks of
antipsychotic treatment [Greenbaum et al., 2007]. Second, variations in the flanking or regulatory regions, rather than in the
genomic region of the PAWR gene, could be related to TD susceptibility. All of the SNPs examined in this study are located within the
gene region. If the actual risk variants are located in the flanking or
regulatory regions of the gene, it may be impossible to unravel their
association with TD. Third, it also needs to be considered before
coming to any conclusions that these might be false negative
findings. The power of this study to detect minor allele differences
between the TD and non-TD groups ranged from 5.5% to 31.4%. If
the PAWR gene does not play a major role in TD, we may not
therefore have enough power to detect it.
In conclusion, we were unable to show an association between
genetic variations in the human PAWR gene and TD. However, the
question of whether the polymorphisms in the PAWR gene are
associated with other mental disorders, such as major depressive
disorder, deserves further study.
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variation, par, analysis, genes, genetics, tardive, pawr, human, schizophrenia, dyskinesia
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