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Association Studies of Genomic Variants with Treatment Response to Risperidone, Clozapine, Quetiapine and Chlorpromazine in the Chinese Han Population

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Association Studies of Genomic Variants with Treatment Response to Risperidone, Clozapine, Quetiapine and Chlorpromazine in the Chinese Han Population The Pharmacogenomics Journal (2016) 16, 357–365 © 2016 Macmillan Publishers Limited All rights reserved 1470-269X/16 www.nature.com/tpj ORIGINAL ARTICLE Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population QXu1,XWu1,MLi1, H Huang2,3, C Minica4,ZYi5, G Wang6, L Shen1, Q Xing7, Y Shi1,LHe1,7,8 and S Qin1,2,3,8 Schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population. Continuous long-term treatment is required to maintain social functioning and prevent symptom relapse of schizophrenia patients. However, there are considerable individual differences in response to the antipsychotic drugs. There is a pressing need to identify more drug-response- related markers. But most pharmacogenomics of schizophrenia have typically focused on a few candidate genes in small sample size. In this study, 995 subjects were selected for discovering the drug-response-related markers. A total of 77 single-nucleotide polymorphisms of 25 genes have been investigated for four commonly used antipsychotic drugs in China: risperidone, clozapine, quetiapine, and chlorpromazine. Significant associations with treatment response for several genes, such as CYP2D6, CYP2C19, COMT, ABCB1, DRD3 and HTR2C have been verified in our study. Also, we found several new candidate genes (TNIK, RELN, NOTCH4 and SLC6A2) and combinations (haplotype rs1544325–rs5993883–rs6269–rs4818 in COMT) that are associated with treatment response to the four drugs. Also, multivariate interactions analysis demonstrated the combination of rs6269 in COMT and rs3813929 in HTR2C may work as a predictor to improve the clinical antipsychotic response. So our study is of great significance to improve current knowledge on the pharmacogenomics of schizophrenia, thus promoting the implementation of personalized medicine in schizophrenia. The Pharmacogenomics Journal (2016) 16, 357–365; doi:10.1038/tpj.2015.61; published online 18 August 2015 INTRODUCTION poor. There is a pressing need to identify more drug-response- Schizophrenia is a chronic and debilitating mental disorder related markers based on which response to treatment can be affecting 1% of the general population, which is often described predicted. And on this basis, a number of pharmacogenetic in terms of both positive and negative symptoms, such as studies have been performed. To date, most studies have typically hallucinations, delusions, thought disorders, avolition and social focused on candidate genes, mainly selected for drug- withdraw, as well as cognitive and functional impairment.1–3 metabolizing enzyme genes, transport genes and neurotransmit- 5 Continuous long-term treatment is required to maintain social ter receptors genes. functioning and prevent symptom relapse, which causes signifi- Several studies have shown positive associations between 6,7 cant public health and economic burden.4 genetic variation and different antipsychotic drug response. Antipsychotic drugs are the mainstay of treatment for schizo- However, these studies mainly focus on a few genes through phrenia. The vast majority of antipsychotic drugs in current use can candidate gene association study method and most were be classified into two categories: first-generation antipsychotic performed in small samples, which make these results could not medications and second-generation antipsychotic medications. be confirmed by diffident groups and be used in clinical practices.4 Currently available antipsychotic drugs achieve a certain degree At present, there is only a few variant that is well replicated and of clinical effective schizophrenia treatment in about 50% of holds promise as clinical biomarkers, such as CYP2D6 and ABCB1.8 patients.2 And treatment failure for schizophrenia might cause In recent years, genome-wide association study, which has the weeks of unremitted illness and potential adverse drug reactions, as potential to discover new molecular markers of drug actions, had well as following larger clinical and economic cost. Risperidone, been applied to antipsychotic response and drug-induced side clozapine, quetiapine and chlorpromazine are the most commonly effect studies. However, these studies were also mainly performed used antipsychotic drugs in China. As with all antipsychotics, there in relatively small samples, which has the low power to uncover are considerable individual differences in response to the four the significant variants, and sometimes genome-wide association – drugs, in terms of both therapeutic effects and adverse effects. study results are not replicated across studies or population.9 11 Identifying the optimal treatment for any patient is often a trial There has been an increasing awareness that larger sample size is and error process that can span a long time, and response is often important for future studies to discover the reliable genomic 1Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China; 2Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 3Broad Institute of Harvard and MIT, Cambridge, MA, USA; 4Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; 5Shanghai Institute of Mental Health, Shanghai, China; 6Nanjing Medical University Affiliated Wuxi Mental Health Center, Wuxi, China; 7Institutes of Biomedical Sciences, Fudan University, Shanghai, China and 8Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China. Correspondence: Dr S Qin, Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Little White House Building 1954 Hua Shan Road, Shanghai 200030, China. E-mail: [email protected] Received 13 April 2015; revised 8 June 2015; accepted 14 July 2015; published online 18 August 2015 Pharmacogenomics of schizophrenia QXuet al 358 variants with treatment response.8 Furthermore, the drug response the end of week 2. After that, the dosage was adjusted according to of antipsychotic drugs involves the process of absorption, individual tolerance. For all the participants, medication compliance was distribution, metabolism, target response and excretion. Also, closely monitored and confirmed by nursing staff, and no other medication genes do not work in isolation, instead, complex molecular was given except trihexylphenidy for extrapyramidal side effects, networks and pathways are often involved in drug response. The clonazepam or lorazepam for insomnia and sennoside for constipation common variants associated with antipsychotics may have smaller during the 2-month study period. Clinical effect was assessed on the Positive and Negative Syndrome Scale effect sizes and combining genetic information may improve their (PANSS), including the positive, negative and general psychopathology global predictive value. A combination of variants in the genes subscales. For all of the recruited patients, clinical assessments were coding for 5-HT2A, 5-HT2C, H2 receptors (histamine receptor type conducted on the day of admission, as well as in the treatment process. All 2) and for the serotonin transporter (serotonin-transporter-linked PANSS ratings were conducted independently by two qualified psychiatrists polymorphic region: HTTLPR) have been reported to result in the who were blind to the genotype of patients. And the inter-rater reliability correct prediction of clozapine response in 76% of cases.12 between the two psychiatrists is good. Treatment efficacy of the four Recently, a great deal of attention has been focused on antipsychotics was measured in terms of the reduction in PANSS scores. pathway-based association analysis for multivariate studies, which Patients were classified as good responders (reduction of PNASS score ⩾ o can combine variants in genes in a known molecular pathway to 50%) and poor responders (reduction of PNASS score 50%) for analysis. test whether the pathway is associated with the phenotype.13,14 Unlike single variant analyses or genome-wide association study, Genotyping which are often underpowered to uncover variants with small Genomic DNA was extracted from the blood samples using the QiaAmpH effect sizes, this approach could provide a more powerful analysis isolation system (Qiagen, Basel, Switzerland). All of the SNPs were for pharmacogenomic analysis. genotyped on the ViiA 7 System (Life Technologies, Carlsbad, CA, USA) In the present study, in order to comprehensively discover the using TaqMan technology. The genotyping probes were designed by the μ predictor of these four antipsychotic drug response, based on Applied Biosystems service. The standard 5 l PCR reaction was carried out pathway approach, genetic variants previously associated with or using TaqMan Universal PCR Master Mix Reagent Kits (Applied Biosystems, Foster City, CA, USA) under the guidelines provided. Genotype accuracy potentially involved in antipsychotic drug response were selected was assessed by re-genotyping within a subsample, and reproducibility for genotyping with Taqman genotyping technology in a relatively was routinely 499%. Genotyping completion rate was 490%. larger schizophrenia subjects. Also, we performed combined analysis of different markers, which lay the foundation for discovering higher predictive value genomic variants with anti-
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