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 x 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 x 10(-8)], rs1471786 in SLC1A1 [p=1.77 x 10(-8)], and rs9291547 in PCDH7 [p=4.48x 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 x 10(-9)], rs1471786 in SLC1A1 [p=2.33 x 10(-9)], rs9291547 in PCDH7 [p=3.24 x rs9291547 in PCDH7 [p=3.24 x 10(-9)], rs12711680 in CNTNAP5 [p=2.12 x 10(-9)], and rs6444970 in TNIK [p=4.85 x 10(-8)]).], rs12711680 in CNTNAP5 [p=2.12 x 10(-8)], and rs6444970 in TNIK [p=4.85 x 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 x 10(-8)), rs16921385 in SLC1A1 was associated with treatment response to risperidone (p=4.40 x 10(-8)), and rs17022006 in CNTN4 was associated with treatment response to aripiprazole (p=2.58 x 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.
基金：
To our knowledge, this study is the largest genome-wide association study so far of treatment response to antipsychotics in patients with schizophrenia. We identified five regions associated with antipsychotic response containing genes related to synaptic function, neurotransmitter receptors, and schizophrenia susceptibility. By analysing genetic components associated with specific antipsychotic responses, we showed that CACNA1C, SLC1A1 , and CNTN4 were associated with treatment response to olanzapine, risperidone, and aripiprazole, respectively. Our results support the hypothesis that the common variants discovered have similar effects on response to several different antipsychotics. Several explanations for the similar effects of SNPs on treatment response are plausible. First, we might have identified patients who had generally satisfactory or unsatisfactory treatment responses. Second, the mechanism of action of antipsychotic drugs might be mediated mainly by the dopamine neurotransmitter system. Furthermore, most of the genes identified were related to synaptic function. CNTNAP5 belongs to the contactin-associated protein family, a multidomain transmembrane protein predominantly expressed in the nervous system 30 that has been implicated in cell adhesion. 31 A non-synonymous SNP (rs17727261) in this gene was reported to be associated with the effects of olanzapine and risperidone on the negative symptoms of schizophrenia in a previous genome-wide association study of antipsychotic treatment in European populations. 14 SNP rs17727261 was monomorphic in Han Chinese populations in the 1000 Genome project. We identified another CNTNAP5 SNP, rs12711680, with genome-wide significance. This trans-ethnic role of CNTNAP5 in treatment response in people with schizophrenia increases our confidence in the authenticity of the identified risk signals. CNTNAP5 is thus probably associated with varied antipsychotic treatment outcomes in patients with schizophrenia. MEGF10 encodes a member of the multiple-epidermal-growth-factor-like domains protein family involved in axon branching, pruning, and cell adhesion, 32 and is essential for astrocyte-mediated elimination of synapses in the adult brain. 33 Our eQTL results suggested that the identified SNP in this gene might affect treatment outcomes through neuronal function or drug metabolism. Although the eQTL results were from European populations, the minor allele frequencies for SNP rs72790443 were similar in European (0·15) and Asian (0·09) ancestries. PCDH7 has also been implicated in the nervous system and in regulation of synaptic plasticity. This gene belongs to the cadherin superfamily, and encodes a membrane-associated glycoprotein that mediates calcium-dependent cell–cell adhesion. 34 Furthermore, PCDH7 inhibits PP1α, a negative downstream regulator affecting long-term potentiation and long-term depression. 35 Therefore, although the SNP in PCDH7 did not have eQTL effects in our sample, further studies of its effect on PCDH7-related signals are justified. TNIK (in which SNP rs6444970 was identified) encodes a protein molecule with both scaffolding and kinase domains that is important in postsynaptic signalling. 36 Knockdown of TNIK in primary cultured neurons decreases surface concentrations of GRIA1 and alters the synchrony of network activity at excitatory synapses. 37 TNIK is also thought to be a crucial synaptic partner for DISC1, a well known risk factor for schizophrenia, and regulates synapse composition and function via DISC1–TNIK interaction. 38 Finally, the fine-mapping tools integrating results of genome-wide association studies and functional annotations to analyse treatment-response-associated loci identified several candidate genes with several lines of supporting evidence, including TNIK, MEGF10 , and SLC1A1 . Overall, our results support the association of these genes with therapeutic responses. Variants in SLC1A1 are associated with response to both general antipsychotic treatments and to risperidone. SLC1A1 encodes EAAT3, a member of the neuronal high-affinity glutamate transporter family that facilitates clearance of glutamate from the synaptic cleft. EAAT3-deficient mice exhibit brain atrophy and behavioural changes including decreased spatial learning abilities and cognitive impairment, 39 and EAAT3 expression decreases in the infralimbic cortex and hippocampus after chronic clozapine or haloperidol treatment. 40 Antagonisation of EAAT3 might disrupt glutamate removal and result in increased synaptic availability of glutamate and glutamatergic action at the postsynaptic neuron. This mechanism is consistent with the diminished glutamate activity model of schizophrenia. 41 Additionally, our discovery of the SNPs rs1691385 and rs1471786 in SLC1A1 —associated with treatment response to risperidone and to general antipsychotic drugs, respectively—is intriguing: these SNPs are in low linkage disequilibrium in Chinese populations ( r 2 =0·011), suggesting possible distinct or multifold mechanisms of SLC1A1 in treatment responses to different antipsychotic drugs. Our antipsychotic-specific analyses showed that CACNA1C was associated with response to olanzapine and CNTN4 with response to aripiprazole. CACNA1C is one of the most important genes for schizophrenia in both European and Chinese populations. 42 It encodes the L-type calcium channel Cav1.2, which is a target for available schizophrenia drugs. CNTN4 has also been associated with schizophrenia, 42 suggesting that the susceptibility genes identified by genome-wide association studies might be potential therapeutic targets. However, we noticed a lack of overlap between identified genome-wide loci affecting the specific treatment responses to each of the seven drugs, for which there are two possible explanations. First, although antipsychotic drugs might act via common pathways, such effects are probably mediated by only a small group of genes. Second, different antipsychotic drugs act via different mechanisms—eg, risperidone is a DRD2 and 5HT2 receptor antagonist, aripiprazole agonises DRD2 and 5HT1A but can also antagonise 5HT2A, olanzapine is a broad-spectrum receptor antagonist. The main potential benefit of our findings might be to guide treatment choice. However, in clinical practice, the effect size of the SNP as a response-related factor might be too small to predict treatment response and to choose the optimal drug. Therefore, we used the genetic risk score approach to construct a predicted treatment response score from all the associated variants. This predicted score (with different thresholds of percentage change of PANSS values) could distinguish responders from non-responders, and might help clinicians to predict treatment responses and choose the most appropriate antipsychotic for patients. Our results suggest that SNPs have scant clinical utility at present, but there is potential for enhanced predictive ability with better understanding of the many variants that might contribute to responses. However, predicted accuracy was still poor and needs to be improved with more significant SNPs and other environmental factors. Our study had several limitations. Although we considered underlying non-genetic factors and used them as covariates, other potential factors, such as smoking, duration of illness, duration of treatment, baseline weight, previous antipsychotics, and concomitant therapy, should be analysed in future studies. Furthermore, although our findings provide new insights into the treatment response to antipsychotic drugs, the susceptibility loci were identified in samples of Han Chinese ancestry. These identified variants might not be associated with treatment response in other ethnic groups. Validation studies in other populations are necessary, not only to investigate whether the identified loci can be generalised to the other ethnicities but also to identify new susceptibility loci for antipsychotic treatment response. In summary, we have identified five genetic loci associated with response to antipsychotic treatment in patients with schizophrenia. Future research should extend these findings to larger samples and different populations to confirm their use in development of personalised medicine. Contributors XM, FY, LL, CW, TLi, DZ, and WY were co-primary investigators. HYu, HYa, LW, JL, TLu, HZ, XX, ML, DZ, and WY designed the study, contributed to analysis and interpretation of data, and wrote the first draft of the Article. HYu, HYa, and WY did the statistical analyses and prepared the tables and figures. HYu and WY provided further data interpretation. LT, WD, QC, GY, FZ, JY, KL, LL, QT, and HZ were responsible for patient recruitment. In-depth phenotyping was carried out by HYu, HYa, LW, JL, and WY. All authors contributed to drafting the work or critically revising it for important intellectual content, and made substantial contributions to the concept and design of the study and data acquisition, analysis, and interpretation. Declaration of interests We declare no competing interests. Acknowledgments This study was funded by the National Key Technology R&D Program of China (2016YFC1307000 and 2015BAI13B01), National Natural Science Foundation of China (81571313 and 91432304), National High Technology Research and Development Program of China (2008AA02Z401 and 2009AA022702), and Beijing Nova Program Interdisciplinary Studies Cooperative Projects (Z161100004916038). We are greatly indebted to all study participants, without whom this research would not have been possible. We thank the following psychiatrists, coordinators, and directors from members of the Chinese Antipsychotics Pharmacogenomics Consortium (psychiatric hospitals and institutions in mainland China) for providing invaluable help over the course of the project: Hongyan Zhang, Yueqin Huang, Jun Yan, Tianmei Si, and Xin Yu (Insitute of Mental Health, Peking University Sixth Hospital); Xun Hu (West China Hospital, Sichuan University); Xue Han and Jiansong Zhou (Second Xiangya Hospital of Central South University); Yunlong Tan (Beijing HuiLongGuan Hospital, Peking University); Yongfeng Yang and Hongxing Zhang(Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China); Bo Du (Hebei Mental Health Center); Guangming Xu (Tianjin Anding Hospital); Cuicui Ma, Chao Jin, Wenbin Ma, and Gang Zhang (Jinzhou Kangning Hospital); Wei Wang, Zaohuo Cheng, and Guoyang Qi (Wuxi Mental Health Center, Nanjing Medical University); Xuebing Chen and Honghui Chen (Wuhan Mental Health Center, Wuhan); Yunchun Chen (First Affiliated Hospital of the Fourth Military Medical University, Xi'an); Rongxin Zhu, Jianxiong Fan, and Ning Zhang (Nanjing Brain Hospital); Liying Yang, Zhiyong Li, and Congpei Zhang (Harbin First Specialized Hospital); Chuanhua Lu, Lei Su, and Jisheng Tang (Shandong Mental Health Center); Yuping Liu and Yuping Ning (Guangzhou Mental Hospital); Shutao Pang, Guanjun Wang, and Shenghai Wang (Qingdao Mental Health Center); Xuanyin Huang and Rongke Wang (Third People's Hospital of Mianyang City); Zhili Zou and Huaqing Meng (First Affiliated Hospital of Chongqing Medical University); Bin Hu and Lihua Yu (Jiangxi Mental Hospital); Guangya Liu and Tiansheng Guo (Hunan Brain Hospital); Bo Wang and Xueqin Yu (Chongqing Mental Health Center); Ying Sun (Liaoning Provincial Mental Health Center); Duanfang Cai and Youguo Tan (Zigong Mental Health Center); Ming Luo and Yueliang Zhang (Third People's Hospital); Xiaoping Ge (Changsha Psychiatry Hospital); Yueqing Ding (Fifth People's Hospital of Jiujiang); Jun Li and Haijun Wang (Veterans' Hospital of Sichuan Province); Deping Chen, Fuhua Zeng, and Jun He (Ziyang Psychiatric Hospital); Yifei Xu and Guangxiang Zheng (Sixth Hospital of Changchun); Wei Jian and Wenjun Mao (Chengdu Mental Health Center); and Shiwu Yang and Chenglin Li (Chengdu Dekang Hospital).
第一作者机构：[1]Peking Univ, Hosp 6, Inst Mental Hlth, Beijing 100191, Peoples R China;[2]Jining Med Univ, Dept Psychiat, Jining, Shandong, Peoples R China;
通讯作者：
通讯机构：[1]Peking Univ, Hosp 6, Inst Mental Hlth, Beijing 100191, Peoples R China;[3]Peking Univ, Minist Hlth, Natl Clin Res Ctr Mental Disorders, Beijing, Peoples R China;[4]Peking Univ, Minist Hlth, Key Lab Mental Hlth, Beijing, Peoples R China;
推荐引用方式(GB/T 7714)：
Yu Hao,Yan Hao,Wang Lifang,et al.Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study[J].LANCET PSYCHIATRY.2018,5(4):327-338.doi:10.1016/S2215-0366(18)30049-X.
APA：
Yu, Hao,Yan, Hao,Wang, Lifang,Li, Jun,Tan, Liwen...&Yue, Weihua.(2018).Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study.LANCET PSYCHIATRY,5,(4)
MLA：
Yu, Hao,et al."Five novel loci associated with antipsychotic treatment response in patients with schizophrenia: a genome-wide association study".LANCET PSYCHIATRY 5..4(2018):327-338
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