Analysis of genetic variations in the human Par-4 (PAWR) gene and tardive dyskinesia in schizophrenia.код для вставкиСкачать
LETTER TO THE EDITOR 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* 1 Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan 2 3 Yuli Mental Health Research Center, Department of Psychiatry, Yuli Veterans Hospital, Yuli, Hualien, Taiwan 4 Institute of Medical Science, Tzu Chi University, Hualien, Taiwan Department of Psychiatry, Pali-Psychiatric Hospital, Taipei, Taiwan 5 6 Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan Received 9 January 2008; Accepted 28 April 2008 TO THE EDITOR: 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 interviews. We selected genotyped genetic markers in a combined CHB and JPT population from the International HapMap Project (http:// www.hapmap.org/). 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. E-mail: email@example.com Published online 27 May 2008 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.b.30795 439 440 AMERICAN JOURNAL OF MEDICAL GENETICS PART B TABLE I. Haplotype Analyses of the PAWR Gene in the TD and Non-TD Groups Haplotype TATGA CGTGA TATAC TGTGA TATGC TACAC Global a TD, % 42.5 18.0 12.8 11.2 8.6 7.0 Non-TD, % 43.5 17.0 14.3 8.2 10.2 6.8 Permutation P-value* 0.807 0.722 0.536 0.160 0.431 0.911 0.754 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.  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. REFERENCES Greenbaum L, Strous RD, Kanyas K, Merbl Y, Horowitz A, Karni O, Katz E, Kotler M, Olender T, Deshpande SN, Lancet D, Ben-Asher E, Lerer B. 2007. Association of the RGS2 gene with extrapyramidal symptoms induced by treatment with antipsychotic medication. Pharmacogenet Genomics 17:519–528. Kovoor A, Seyffarth P, Ebert J, Barghshoon S, Chen CK, Schwarz S, Axelrod JD, Cheyette BN, Simon MI, Lester HA, Schwarz J. 2005. 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