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Genetic and Epigenetic Influences on Schizotypal Cognition

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Genetic and Epigenetic Influences on Schizotypal Cognition by Emma Leah Leach B.Sc. (Hons., Biology), University of Western Ontario, 2011 Thesis Submitted In Partial Fulfillment of the Requirements for the Degree of Master of Science in the Department of Biological Sciences Faculty of Science Emma Leah Leach 2013 SIMON FRASER UNIVERSITY Summer 2013 Approval Name: Emma Leah Leach Degree: Master of Science (Biology) Title of Thesis: Genetic and Epigenetic Influences on Schizotypal Cognition Examining Committee: Chair: Dr. Gerhard Gries Professor Dr. Bernard Crespi Senior Supervisor Professor Dr. Felix Breden Supervisor Professor, Departmental Chair Dr. Gratien Prefontaine Supervisor Assistant Professor Dr. Julian Christians Internal Examiner Associate Professor Department of Biological Sciences Date Defended/Approved: August 13, 2013 ii Partial Copyright Licence iii Ethics Statement The author, whose name appears on the title page of this work, has obtained, for the research described in this work, either: a. human research ethics approval from the Simon Fraser University Office of Research Ethics, or b. advance approval of the animal care protocol from the University Animal Care Committee of Simon Fraser University; or has conducted the research c. as a co-investigator, collaborator or research assistant in a research project approved in advance, or d. as a member of a course approved in advance for minimal risk human research, by the Office of Research Ethics. A copy of the approval letter has been filed at the Theses Office of the University Library at the time of submission of this thesis or project. The original application for approval and letter of approval are filed with the relevant offices. Inquiries may be directed to those authorities. Simon Fraser University Library Burnaby, British Columbia, Canada update Spring 2010 Abstract Genetically-based risk for schizophrenia, a highly polygenic condition, may contribute to a continuum of schizophrenia-related phenotypes between clinical populations and healthy populations. Using data from the literature as well as novel genotype and methylation data, I present evidence that schizophrenia risk alleles influence cognition in non-clinical populations, both individually, and together. Additionally, I find evidence that these alleles may be maintained across evolutionary time due to benefits in terms of enhanced performance in particular cognitive domains. Further, I demonstrate effects of genetic and epigenetic variation in the imprinted gene LRRTM1 on schizotypy and handedness. These results demonstrate that schizophrenia risk alleles influence not only increased disease risk but are also associated with cognitive performance and schizotypal traits in the general population. Keywords: schizophrenia; schizotypy; risk allele; genetic risk score; cognitive performance; imprinting iv Acknowledgements I am deeply grateful to everyone who has contributed to the completion of my thesis. Bernie Crespi, my supervisor, has inspired me with his ability to creatively integrate his vast knowledge and pose intriguing scientific questions. I appreciate his constant support and the dedication his time and patience to nurture my learning and academic growth. I would also like to thank Gratien Prefontaine as a mentor, who has provided much needed molecular biology advice at a moment‟s notice. I am indebted to Silven Read, who has always made herself available to help me and her assistance has been invaluable in the timely completion of this thesis. I would also like to thank Shabnam Massah and Aydn Bekirov for their expertise and assistance in teaching me new techniques. Peter Hurd and his students have made an important contribution by providing much of the data contributed to this thesis and I am grateful for this collaboration. I have thoroughly enjoyed the time I have spent getting to know the members of the Human Evolutionary Studies Program (HESP) and FAB* Lab. I am especially appreciative of their insightful feedback on my work. I am thankful to NSERC for funding my research and to HESP for providing me with a graduate fellowship. As well, thank you to Marlene Nguyen and the biology office staff for their assistance throughout my time at SFU. I feel blessed to have had the support and encouragement of my loving parents and sisters in everything I do. Finally, I am immensely grateful to Jeremy Kawahara, who has been by my side from start to finish with his interest, encouragement, technical support, and solidarity. v Table of Contents Approval .......................................................................................................................... ii Partial Copyright Licence ................................................................................................ iii Abstract .......................................................................................................................... iv Acknowledgements ......................................................................................................... v Table of Contents ........................................................................................................... vi List of Tables ................................................................................................................ viii List of Figures ................................................................................................................. ix 1. Introduction ........................................................................................................... 1 1.1. References ............................................................................................................. 3 2. The effects of schizophrenia risk alleles on cognitive task performance .......................................................................................................... 5 2.1. Abstract .................................................................................................................. 5 2.2. Introduction ............................................................................................................. 6 2.3. Methods .................................................................................................................. 8 2.3.1. Statistical Analysis ....................................................................................... 9 2.4. Results ................................................................................................................. 10 2.4.1. Overall cognitive performance by risk-allele carriers .................................. 10 1) Deleterious allele hypothesis ................................................................. 10 2) Conditionally-beneficial allele hypothesis .............................................. 10 3) Resilience hypothesis ........................................................................... 11 4) Sensitivity hypothesis ............................................................................ 11 2.4.2. Contrasting effects of specific SNPs in patients and controls..................... 13 1) Deleterious allele hypothesis ................................................................. 13 2) Conditionally-beneficial allele hypothesis .............................................. 13 3) Resilience hypothesis ........................................................................... 13 4) Sensitivity hypothesis ............................................................................ 14 2.4.3. Variation among domains of cognitive performance .................................. 16 2.4.4. Effects of sample size on performance ...................................................... 18 2.4.5. Contrasting effects of SNPs ...................................................................... 19 2.5. Discussion ............................................................................................................ 19 2.6. References ........................................................................................................... 22 2.7. Appendix A ........................................................................................................... 25 Studies cited in the literature review described in Chapter 2...................... 47 3. Schizotypy, cognitive performance, and genetic risk for schizophrenia in a non-clinical population ................................................................................ 57 3.1. Abstract ................................................................................................................ 57 3.2. Introduction ........................................................................................................... 58 3.3. Methods ................................................................................................................ 60 3.3.1. Sample ...................................................................................................... 60 3.3.2. Genetic Data ............................................................................................. 61 3.3.3. Genetic Risk Score Calculations ............................................................... 61 3.3.4. Psychometric Measures ............................................................................ 62 vi 3.4. Results ................................................................................................................. 63 3.4.1. Schizotypy ................................................................................................
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