Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population.
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 advance online publication, 18 August 2015; doi:10.1038/tpj.2015.61.
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
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Xu
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
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Wu
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
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Li
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of Harvard and MIT, Cambridge, MA, USA.
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Huang
Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
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Minica
Shanghai Institute of Mental Health, Shanghai, China.
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Yi
Nanjing Medical University Affiliated Wuxi Mental Health Center, Wuxi, China.
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Wang
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
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0000-0002-0659-2399
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Shen
Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
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Xing
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
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Shi
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, China.|Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China.
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He
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of Harvard and MIT, Cambridge, MA, USA.|Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China.
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D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics*; D016009:Chi-Square Distribution; D002681:China; D002746:Chlorpromazine / Q000627:therapeutic use*; D003024:Clozapine / Q000627:therapeutic use*; D003430:Cross-Sectional Studies; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D000069348:Quetiapine Fumarate / Q000627:therapeutic use*; D000091042:Reelin Protein; D012307:Risk Factors; D018967:Risperidone / Q000627:therapeutic use*; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome; D055815:Young Adult
D014150:Antipsychotic Agents; D000091042:Reelin Protein; D000069348:Quetiapine Fumarate; C000717127:RELN protein, human; D003024:Clozapine; D018967:Risperidone; D002746:Chlorpromazine