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This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Trajectories of DNA Methylation Associated with Clozapine Exposure and Clinical Outcomes Gillespie, Amy Louise Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 30. Sep. 2021 List of Tables TRAJECTORIES OF DNA METHYLATION ASSOCIATED WITH CLOZAPINE EXPOSURE AND CLINICAL OUTCOMES Amy Gillespie INSTITUTE OF PSYCHIATRY PSYCHOLOGY AND NEUROSCIENCE, KING'S COLLEGE - 1 - List of Tables Contents List of Tables ..................................................................................................................................... 6 List of Figures .................................................................................................................................... 7 List of Abbreviations ......................................................................................................................... 8 Abstract .......................................................................................................................................... 10 Acknowledgements ........................................................................................................................ 11 1 Introduction .......................................................................................................................... 13 1.1 Schizophrenia .................................................................................................................... 13 1.2 Treatment-resistant schizophrenia ................................................................................... 13 1.2.1 Defining treatment-resistant schizophrenia ............................................................. 14 1.2.2 Significance of treatment-resistant schizophrenia ................................................... 17 1.3 Clozapine ........................................................................................................................... 17 1.4 What is DNA methylation and why study its role in clozapine? ....................................... 21 1.4.1 The genome and gene expression ............................................................................ 21 1.4.2 Genetic variation and schizophrenia ........................................................................ 24 1.4.3 The epigenome ......................................................................................................... 28 1.4.4 Epigenetic variation and schizophrenia .................................................................... 31 2 Overall Method ..................................................................................................................... 38 2.1 Longitudinal study ............................................................................................................. 38 2.1.1 Study design .............................................................................................................. 38 2.1.2 Participants ............................................................................................................... 41 2.1.3 Clinical assessments .................................................................................................. 44 2.1.4 Blood samples ........................................................................................................... 47 2.1.5 Quality control (QC) assessments ............................................................................. 51 2.1.6 Power ........................................................................................................................ 52 2.2 Cross-sectional dataset ..................................................................................................... 55 2.3 Summary ........................................................................................................................... 55 - 2 - List of Tables 3 Exposure to Clozapine and Associated DNA Methylation Changes ...................................... 56 3.1 Background: Exposure to clozapine .................................................................................. 56 3.1.1 Existing epigenetic research...................................................................................... 57 3.2 Statistical method: Exposure to clozapine ........................................................................ 62 3.3 Results: Time on clozapine (weeks) .................................................................................. 64 3.3.1 Participant characteristics (time on clozapine) ......................................................... 64 3.3.2 Global DNA methylation (time on clozapine) ........................................................... 73 3.3.3 Differentially methylated positions (time on clozapine) .......................................... 74 3.3.4 Pathway analysis (time on clozapine) ....................................................................... 81 3.3.5 Candidate CpG site methylation (time on clozapine) ............................................... 84 3.3.6 Comparison to cross-sectional data (time on clozapine) .......................................... 85 3.4 Results: Clozapine levels ................................................................................................... 87 3.4.1 Participant characteristics (clozapine levels) ............................................................ 87 3.4.2 Global DNA methylation (clozapine levels) ............................................................... 91 3.4.3 Differentially methylated positions (clozapine levels) .............................................. 91 3.4.4 Pathway analysis (clozapine levels) .......................................................................... 99 3.4.5 Candidate CpG site methylation (clozapine levels)................................................. 102 3.4.6 Comparison to cross-sectional data (clozapine levels) ........................................... 103 3.5 Discussion: Exposure to clozapine .................................................................................. 106 3.5.1 Time on clozapine ................................................................................................... 106 3.5.2 Clozapine level ........................................................................................................ 111 3.5.3 Summary ................................................................................................................. 114 4 Therapeutic Response to Clozapine and Associated DNA Methylation Changes ............... 116 4.1 Background: Therapeutic response to clozapine ............................................................ 116 4.1.1 Defining response to clozapine ............................................................................... 116 4.1.2 Physiological changes associated with response to clozapine ............................... 118 4.1.3 Genetic variation associated with response to clozapine ...................................... 119 4.1.4 Epigenetic variation associated with response to clozapine .................................. 123 - 3 - List of Tables 4.2 Statistical method: Therapeutic response to clozapine .................................................. 124 4.3 Results: Percentage change in response to clozapine (between-individuals) ................ 128 4.3.1 Responders vs non-responders (categorical) .......................................................... 128 4.3.2 Change in total symptom severity (continuous) ..................................................... 152 4.3.3 Change in psychosocial functioning (continuous)................................................... 158 4.3.4 Change in quality of life (continuous) ..................................................................... 163 4.4 Results: Symptom severity (within individuals) .............................................................. 168 4.4.1 Participant characteristics ....................................................................................... 168 4.4.2 Total symptom severity .......................................................................................... 168 4.4.3 Positive symptom severity ...................................................................................... 180 4.4.4 Negative symptom severity ...................................................................................
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