非典型抗精神病药物所致体重增加的遗传易感区域精细定位研究

Antipsychotic induced weight gain (AIWG) is a common and difficult phenomenon in psychiatric treatment, and genetic factors play an important role in AIWG. Previously, we have performed a pharmacogenomics study of antipsychotic drugs in 3564 patients with schizophrenia (SCH). Furthermore, we screened the susceptibility regions of AIWG using the fine mapping method, and identified multiple susceptibility loci. However, these loci need to be further validated. On the basis of our previous work, the present project intends to carry out the following researches. 1) We will recruited 800 first-episode and drug-naïve patients with SCH. Patients who met inclusion criteria will be treated with risperidone for eight weeks. On the basis of clinical data and genetic samples, we will systematically validate the associations between susceptibility loci and AIWG. 2) Based on the validated susceptibility loci, we will establish the mathematical prediction model of AIWG using genetic risk score and machine learning method. Then, the accuracy of the model will also be tested in an independent sample. 3) To explore the genetic mechanism of susceptibility loci, we will use bioinformatics database (e.g., ENCODE) and molecular biology technology to explore the functions of the susceptible loci. This project is expected to preliminarily confirm the susceptibility loci and their combinations of AIWG. It will help explaining the genetic mechanism of AIWG and provide theoretical basis for individualized medicine.

抗精神病药所致体重增加（AIWG）是精神科治疗中普遍又棘手的现象，遗传因素在其中起重要作用。本项目组前期已开展共计3564例精神分裂症（SCH）患者的药物基因组学研究，并采用精细定位方法全面筛查AIWG易感区域，筛选出多个易感位点，但有待进一步验证。在前期工作基础上，本项目组拟开展如下研究：1）收集800例首发未用药SCH患者，利培酮单药治疗8周，并在随访数据和遗传样本基础之上，系统性验证前期精细定位后的易感位点与AIWG的关联性；2）针对验证后的易感位点，采用多基因风险评分和机器学习等方法建立AIWG的数学预测模型，利用独立样本检验该模型的准确性；3）通过生物信息学数据库（ENCODE等）和分子生物学技术，对验证后的易感位点展开系统的功能分析，探讨其如何参与AIWG的发生发展。本项目预期将初步确定AIWG的易感位点及其组合，有助于明确AIWG的遗传机制，为个性化用药指导提供理论依据。

非典型抗精神病药在精神分裂症的治疗中作用显著，但是许多患者服用抗精神病药后出现体重明显增加，心脑血管、糖尿病等患病风险大大提高。抗精神病药所致体重增加（AIWG）是精神科治疗中普遍又棘手的现象，遗传因素在其中起重要作用。本项目组收集精神分裂症患者急性期治疗随访数据和血样，在随访数据和遗传样本基础之上，采用精细定位方法全面筛查AIWG易感区域，筛选出PTPRD和PEPD等基因上的易感位点，并在独立样本中系统性验证前期精细定位后的易感位点与AIWG的关联性；针对已验证后的易感位点，采用多基因风险评分等方法建立AIWG的预测模型，利用独立样本检验该模型的准确性；通过孟德尔随机化分析和共定位分析等技术，对验证后的易感位点展开系统的功能分析，探讨其如何参与AIWG的发生发展。本项目初步确定AIWG的易感位点及其组合，有助于明确AIWG的遗传机制，为个性化用药指导提供理论依据。