Pharmacogenetics of psychotropic drugs and genetic influences on adverse drug reactions

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.