Pharmacogenetics of psychotropic drugs and genetic influences on adverse drug reactions

我研究了遗传变异对精神药物不良反应的影响，重点是精神药物的代谢副作用和抑郁症睡眠障碍的遗传学基础。除了回顾已发表的文献外，我主要从四个方面考虑了这个研究课题。第一章是CYP2D6基因变异对抗精神病药致高泌乳素血症影响的系统综述和荟萃分析，这是一种相对常见但研究不足的不良反应。第二章和第三章基于英国生物银行（UK Biobank）的数据，我在那里对已知的药原及其与两种常见药物不良反应（增加糖尿病风险和睡眠障碍）的关联进行了假设驱动的分析。在这个项目的工作中，两个关键的限制变得明显。首先，假设驱动或“候选基因”方法可能会限制发现具有药物遗传学重要性的新基因座。其次，我对英国生物银行横断面数据的分析性质使得很难对任何观察结果的因果方向得出明确的结论。因此，第四章和第五章旨在解决这些限制。第四章建立在我对抗抑郁药引起的睡眠障碍的药物遗传学分析的基础上，通过对自我报告的睡眠持续时间的全基因组关联研究，分析睡眠和抑郁之间的遗传相关性，以及孟德尔随机化分析来考虑这些关联的因果方向。在第五章中，我描述了一项临床研究的建立，以评估精神病人群体的药物遗传干预措施。尽管由于COVID-19大流行期间暂停招募，可用于分析的数据有限，但我描述了该研究的科学依据，概述了为建立和获得该研究的伦理批准而开展的工作，以及为在NHS中实施药物遗传学测试起草临床指南的邻近项目。

I investigate the impact of genetic variation on adverse drug reactions to psychotropic medications, with a focus on the metabolic-side effects of psychotropic drugs and the genetics basis of sleep disturbance in depression. In addition to reviewing published literature, I have considered this research topic in four main ways. Chapter one is a systematic review and meta-analysis of the impact of CYP2D6 genetic variation on antipsychotic-induced hyperprolactinaemia, which is a relatively common but understudied adverse-drug reaction. Chapters two and three are based on data from UK Biobank, where I have conducted a hypothesis-driven analysis of known pharmacogenes and their association with two common adverse drug reactions: increased diabetes risk and sleep disturbance. In working on this project, two key limitations became apparent. Firstly, the hypothesis-driven or 'candidate-gene' approach may limit discovery of novel loci of pharmacogenetic importance. Secondly, the nature of my analysis of cross-sectional UK Biobank data makes it difficult to draw firm conclusions on the causal direction of any observations. Therefore, chapters four and five aim to address these limitations. Chapter four builds on my pharmacogenetic analysis of antidepressant-induced sleep disturbance via a genome-wide association study of self-reported sleep duration, with an analysis of the genetic correlation between sleep and depression, as well Mendelian randomisation analyses to consider the causal direction of these association. In chapter five, I describe the set-up of a clinical study to assess pharmacogenetic interventions in a psychiatric patient population. Although limited data is available for analysis due to a pause in recruitment during the COVID-19 pandemic, I describe scientific rationale for the study and outline the work conducted to set-up and gain ethical approvals for the study, as well as an adjacent project to draft clinical guidelines for the implementation of pharmacogenetic testing in the NHS.