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Title: Trajectories of DNA methylation associated with clozapine exposure and clinical outcomes
Author: Gillespie, Amy Louise
ISNI:       0000 0004 7660 0715
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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Clozapine is an atypical antipsychotic known to be uniquely effective in patients with treatment-resistant schizophrenia, but associated with numerous adverse reactions. Despite substantial research efforts, we lack a full understanding of the mechanistic processes underlying clozapine's efficacy and identification of the most relevant mechanisms. Animal studies suggest that clozapine induces changes in DNA methylation (a dynamic epigenetic modification which can regulate gene expression). However, research in humans is extremely limited. This thesis provides an original contribution to the literature as the first study to report positions of significant differences in longitudinal DNA methylation trajectories associated with clozapine exposure, therapeutic response and adverse reactions. 22 participants with schizophrenia were recruited and within-participant sampling was conducted before clozapine initiation and at three time-points over the subsequent six months. The Illumina 450k array was used to assay epigenome-wide DNA methylation in 85 samples of whole blood. I conducted multi-level regression models and pathway analysis. Across all models, I identified 33 epigenome-wide significant (p < 1*10-7) differently methylated positions (DMPS), with over-representation of DMPS indicated to have correlated methylation in brain tissue. DMPs located on genes involved in signal transduction, glutamatergic and GABAergic systems, calcium signalling, glucose homeostasis, immune function and transcription regulation were associated with both clozapine exposure and therapeutic efficacy. Additionally, DMPs located on genes involved in cell adhesion, glycine and neuronal development were associated specifically with therapeutic efficacy. DMPs located on genes involved in immune function and signal transduction were associated with drowsiness, increased appetite and weight, and cardiovascular symptoms. DMPs located on genes involved in energy metabolism were associated with increases in appetite and weight. These results align with literature suggesting that clozapine normalises schizophrenia-associated disruption in glutamatergic and GABAergic systems, calcium signalling and immune function; however, further studies of gene expression and downstream effects are required to establish the causal role of DNA methylation.
Supervisor: MacCabe, James Hunter ; Mill, Jonathan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available