Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study.,The Lancet

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Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study.
The Lancet ( IF 168.9 ) Pub Date : 2018-03-01 , DOI: 10.1016/s2215-0366(18)30049-x
Hao Yu ₁ , Hao Yan ₂ , Lifang Wang ₂ , Jun Li ₂ , Liwen Tan ₃ , Wei Deng ₄ , Qi Chen ₅ , Guigang Yang ₆ , Fuquan Zhang ₇ , Tianlan Lu ₂ , Jianli Yang ₈ , Keqing Li ₉ , Luxian Lv ₁₀ , Qingrong Tan ₁₁ , Hongyan Zhang ₂ , Xiao Xiao ₁₂ , Ming Li ₁₃ , Xin Ma ₁₄ , Fude Yang ₆ , Lingjiang Li ₃ , Chuanyue Wang ₁₄ , Tao Li ₄ , Dai Zhang ₁₅ , Weihua Yue ₂ ,

Affiliation

Institute of Mental Health, Peking University Sixth Hospital, Beijing, China; Department of Psychiatry, Jining Medical University, Jining, Shandong, China.
Institute of Mental Health, Peking University Sixth Hospital, Beijing, China; National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing, China.
Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Mental Health Center and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, China.
Beijing Anding Hospital, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China; Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Center for Biological Psychiatry, Beijing HuiLongGuan Hospital, Beijing, China.
Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China.
Institute of Mental Health, Tianjin Anding Hospital, Tianjin, China; Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China.
Hebei Mental Health Center, Baoding, Hebei, China.
Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
Beijing Anding Hospital, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
Institute of Mental Health, Peking University Sixth Hospital, Beijing, China; National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing, China; Peking University-Tsinghua University Joint Center for Life Sciences/ PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.

BACKGROUND Antipsychotic drugs improve schizophrenia symptoms and reduce the frequency of relapse, but treatment response is highly variable. Little is known about the genetic factors associated with treatment response. We did a genome-wide association study of antipsychotic treatment response in patients with schizophrenia. METHODS The discovery cohort comprised patients with schizophrenia from 32 psychiatric hospitals in China that are part of the Chinese Antipsychotics Pharmacogenomics Consortium. Patients who met inclusion criteria were randomly assigned (1:1:1:1:1:1) to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and haloperidol or perphenazine; those assigned to haloperidol or perphenazine were subsequently assigned [1:1] to one or the other) for 6 weeks. Antipsychotic response was quantified with percentage change on the Positive and Negative Syndrome Scale. Single-nucleotide polymorphisms (SNPs) were tested for their association with treatment response. Linkage-disequilibrium-independent SNPs that exhibited potential associations (ie, p<1 × 10-5) were tested in a validation cohort comprising patients from the Chinese Antipsychotics Pharmacogenetics Consortium from five collaborative hospitals, who were treated with olanzapine, risperidone, or aripiprazole for 8 weeks. FINDINGS The discovery cohort contained 2413 patients and the validation cohort 1379 patients. In the discovery cohort, we identified three novel SNPs (rs72790443 in MEGF10 [p=1·37 × 10-8], rs1471786 in SLC1A1 [p=1·77 × 10-8], and rs9291547 in PCDH7 [p=4·48 × 10-8]) that were associated with antipsychotic treatment response at a genome-wide significance level. These associations were confirmed in the validation cohort (p<0·05). In the combined sample of the discovery and validation cohorts, we identified five novel loci showing genome-wide significant associations with general antipsychotic treatment response (rs72790443 in MEGF10 [p=1·40 × 10-9], rs1471786 in SLC1A1 [p=2·33 × 10-9], rs9291547 in PCDH7 [p=3·24 × 10-9], rs12711680 in CNTNAP5 [p=2·12 × 10-8], and rs6444970 in TNIK [p=4·85 × 10-8]). In antipsychotic-specific groups, after the combination of results from both samples, the rs2239063 SNP in CACNA1C was associated with treatment response to olanzapine (p=1·10 × 10-8), rs16921385 in SLC1A1 was associated with treatment response to risperidone (p=4·40 × 10-8), and rs17022006 in CNTN4 was associated with treatment response to aripiprazole (p=2·58 × 10-8). INTERPRETATION We have identified genes related to synaptic function, neurotransmitter receptors, and schizophrenia risk that are associated with response to antipsychotics. These findings improve understanding of the mechanisms underlying treatment responses, and the identified biomarkers could eventually guide choice of antipsychotic in patients with schizophrenia. FUNDING National Key Technology R&D Program of China, National Natural Science Foundation of China.

更新日期：2018-03-24

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