Hao Yu, Lifang Wang1, Luxian Lv2, Cuicui Ma3, Bo Du4, Tianlan Lu1, Chao Jin3, Hao Yan1, Yongfeng Yang2, Wenqiang Li2, Yanyan Ruan1, Hongyan Zhang1, Hongxing Zhang2, Weifeng Mi1, Bryan Mowry5, Wenbin Ma3, Keqing Li4, Dai Zhang6, Weihua Yue7. 1. Peking University Sixth Hospital, Institute of Mental Health, Beijing, China; Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders, Peking University, Beijing, China; 2. Department of Psychiatry of the Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China; Henan Mental Hospital, Henan Key Lab of Biological Psychiatry, Xinxiang, Henan, China; 3. Jinzhou Kangning Hospital, Jinzhou, Liaonin, China; 4. Hebei Mental Health Center, Baoding, Hebei, China; 5. Queensland Brain Institute, University of Queensland, Brisbane, Australia; Queensland Centre for Mental Health Research, The Park - Centre for Mental Health, Wacol, Queensland, Australia; 6. Peking University Sixth Hospital, Institute of Mental Health, Beijing, China; Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences/PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China. 7. Peking University Sixth Hospital, Institute of Mental Health, Beijing, China; Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders, Peking University, Beijing, China; dryue@bjmu.edu.cn.
Abstract
BACKGROUND: Antipsychotic-induced weight gain (AIWG) is a serious concern in therapy with antipsychotic medications. To identify single nucleotide polymorphisms (SNPs) associated with AIWG, we conducted a genome-wide association study (GWAS) for antipsychotic treatment. METHODS: The discovery cohort consisted of 534 patients with schizophrenia, who underwent 8-week treatment with antipsychotics and were genotyped using the Illumina Human 610-Quad BeadChip. The independent replication cohort consisted of 547 patients with schizophrenia, treated with similar antipsychotics, and genotyped using the Sequenom MassARRAY platform. Two hundred and thirty-six drug-naive patients treated with risperidone or quetiapine were analyzed independently. Additionally, we conducted pathway and expression analyses using several public bioinformatics databases. RESULTS: After correction for age and gender, the top 2 genome-wide significant SNPs with AIWG were located in the PTPRD gene (protein tyrosine phosphatase, receptor type D, 9p24-p23; rs10977144, P GWAS = 9.26E-09; rs10977154, P GWAS = 4.53E-08). The third most significant SNP was in the GFPT2 gene (glutamine-fructose-6-phosphate amidotransferase 2, 5q35.3; rs12386481, P GWAS = 1.98E-07). These results were validated in the replication cohort (rs10977144, P Replication = 4.30E-03; rs10977154, P Replication = 6.33E-03; rs12386481, P Replication =7.65E-03). These results were also verified in those patients initially exposed to risperidone and quetiapine (rs10977144, P = 1.97E-05; rs10977154, P = 2.04E-05; rs12386481, P = 1.97E-04). Pathway analyses showed that AIWG may involve in multiple pathways related to metabolic processes. Moreover, PTPRD mRNA might be highly expressed in brain regions, and the SNPs (rs10977144, rs1097154) also showed significant expression quantitative trait locus effects. CONCLUSIONS: Our findings indicate that PTPRD polymorphisms might modulate AIWG.
BACKGROUND: Antipsychotic-induced weight gain (AIWG) is a serious concern in therapy with antipsychotic medications. To identify single nucleotide polymorphisms (SNPs) associated with AIWG, we conducted a genome-wide association study (GWAS) for antipsychotic treatment. METHODS: The discovery cohort consisted of 534 patients with schizophrenia, who underwent 8-week treatment with antipsychotics and were genotyped using the Illumina Human 610-Quad BeadChip. The independent replication cohort consisted of 547 patients with schizophrenia, treated with similar antipsychotics, and genotyped using the Sequenom MassARRAY platform. Two hundred and thirty-six drug-naive patients treated with risperidone or quetiapine were analyzed independently. Additionally, we conducted pathway and expression analyses using several public bioinformatics databases. RESULTS: After correction for age and gender, the top 2 genome-wide significant SNPs with AIWG were located in the PTPRD gene (protein tyrosine phosphatase, receptor type D, 9p24-p23; rs10977144, P GWAS = 9.26E-09; rs10977154, P GWAS = 4.53E-08). The third most significant SNP was in the GFPT2 gene (glutamine-fructose-6-phosphate amidotransferase 2, 5q35.3; rs12386481, P GWAS = 1.98E-07). These results were validated in the replication cohort (rs10977144, P Replication = 4.30E-03; rs10977154, P Replication = 6.33E-03; rs12386481, P Replication =7.65E-03). These results were also verified in those patients initially exposed to risperidone and quetiapine (rs10977144, P = 1.97E-05; rs10977154, P = 2.04E-05; rs12386481, P = 1.97E-04). Pathway analyses showed that AIWG may involve in multiple pathways related to metabolic processes. Moreover, PTPRD mRNA might be highly expressed in brain regions, and the SNPs (rs10977144, rs1097154) also showed significant expression quantitative trait locus effects. CONCLUSIONS: Our findings indicate that PTPRD polymorphisms might modulate AIWG.
Keywords:
D (PTPRD); antipsychotic-induced weight gain (AIWG); genome-wide association study; protein tyrosine phosphatase; receptor type; schizophrenia
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