Effect of Damaging Rare Mutations in Synapse-Related Gene Sets on Response to Short-term Antipsychotic Medication in Chinese Patients With Schizophrenia

作者：Qiang Wang, Hei Man Wu, Weihua Yue, Hao Yan, Yamin Zhang, Liwen Tan, Wei Deng, Qi Chen, Guigang Yang, Tianlan Lu, Lifang Wang, Fuquan Zhang, Jianli Yang, Keqing Li, Luxian Lv, Qingrong Tan, Hongyan Zhang, Xin Ma, Fude Yang, Lingjiang Li, Chuanyue Wang, Xiaohong Ma, Liansheng Zhao, Hongyan Ren, Hao Yu, Yingcheng Wang, Xun Hu, Dai Zhang, Pak C. Sham, Tao Li · 发表于：JAMA Psychiatry · 年份：2018 · DOI：10.1001/jamapsychiatry.2018.3039 · 被引用次数：40 · 研究领域：Schizophrenia research and treatment、Genetic Associations and Epidemiology、Phosphodiesterase function and regulation

Importance: The underlying mechanism for individual differences in patient response to antipsychotic medication remains unknown. Objective: To discover genes and gene sets harboring rare variants associated with short-term antipsychotic medication efficacy. Design, Setting, and Participants: In this multicenter, open-label, randomized clinical trial conducted between July 6, 2010, and December 31, 2011, 3023 patients recruited in China of Chinese Han descent with schizophrenia with total Positive and Negative Syndrome Scale (PANSS) score ≥ 60 received a 6-week treatment of antipsychotic medications randomly chosen from 5 atypical and 2 typical antipsychotic medications. Whole-exome sequencing (WES) was performed in 316 participants (grouped into those with the best response [n=156] and those who had no response [n=160] to the antipsychotic medication prescribed), according to the total PANSS score reduction rate after 6 weeks of treatment. Validation was performed using targeted sequencing in an independent sample of 1920 patients. Data analyses was performed between March 15, 2016, and March 1, 2017. Main Outcomes and Measures: Drug efficacy at week 6 was assessed according to the change in PANSS scores from baseline. Extremely good and extremely poor responders were selected for an initial WES association study, from which a subset of genes showing putative association was selected for independent replication with a targeted sequencing approach. Results: Of the 3023 patient...