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Genetics Factors Contributing to Body Weight in Anorexia Nervosa And Genetics Factors Contributing to Body Weight in Anorexia Nervosa and Bulimia Nervosa by Zeynep Yilmaz A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy (PhD) Institute of Medical Science University of Toronto © Copyright by Zeynep Yilmaz (2013) Genetic Factors Contributing to Body Weight in Anorexia Nervosa and Bulimia Nervosa Zeynep Yilmaz Doctor of Philosophy (PhD) Institute of Medical Science University of Toronto 2013 Abstract Anorexia nervosa (AN) is an eating disorder (ED) with substantial morbidity and the highest mortality among psychiatric disorders. Low body mass index (BMI) is the sine qua non of AN, and behaviours associated with reaching it are the primary reason for AN’s high morbidity and mortality. Low BMI is also the main criterion diagnostically separating AN from bulimia nervosa (BN). The aim of this dissertation was to determine the role of genes regulating weight and appetite in BMI in AN and BN. Study 1 utilized carefully selected DNA samples to explore the role of markers in the leptin, melanocortin, and neurotrophin system genes with known or putative function in AN, BN, and controls, as well as in lifetime BMIs in EDs. Study 2 investigated dopamine pathway genes and FTO in weight regulation in a large sample of AN cases. The results revealed that an MC4R variant linked to antipsychotic-induced weight gain was underrepresented in AN, and AGRP and NTRK2 genetic variants were linked to minimum BMI in AN and maximum BMI in BN, respectively. In Study 2, a significant association between FTO and BMI at recruitment was observed. To our knowledge, this is the first study to utilize two distinct but complementary genetic approaches in the study of weight in EDs. These genetic findings ii may serve as an important first step toward gaining a better understanding of weight regulation in AN and BN, as well as having the potential for developing more effective treatment options and providing a highly specific target for novel medications. Alongside this work, other ED genetic studies utilizing different clinical phenotypes were also carried out during my PhD, and the papers published are inserted as appendices for reasons of thematic unity. iii Acknowledgements First and foremost, I would like to thank my primary PhD supervisor Dr. Allan S. Kaplan, to whom I am forever indebted for his mentorship, encouragement, guidance and support with my research and career path, as well as for his unwavering faith in me even during the times I doubted my own abilities. I would also like to thank my PhD co-supervisor Dr. James L. Kennedy for sharing his vast expertise in psychiatric genetics and warmly welcoming me to his Neurogenetics family. I am grateful for the tremendous expertise, guidance, and support of my Program Advisory Committee members Drs. Robert D. Levitan and Jo Knight. Thank you to Dr. Caroline Davis for being a wonderful external resource and supportive collaborator. I would also like to acknowledge the examiners who have participated in my PhD transfer exam and defense: Drs. Brenda Toner, Gary Rodin, Franco Vaccarino, Lucy Osborne, and Howard Steiger. This PhD project would not have happened without the support of the Price Foundation Consortium and Genetic Consortium for Anorexia Nervosa. I would like to thank Drs. Andrew W. Bergen, Walter H. Kaye, Pierre Magistretti, Hakon Hakonarson, and the Price Foundation collaborators for making my PhD possible. I would also like to acknowledge Mme Luciana Price for generously funding this genetic consortium in an era when eating disorders were not thought to have a strong genetic basis. As for the Genetic Consortium for Anorexia Nervosa, I am grateful for the guidance and endless support of Dr. Cynthia M. Bulik. Thank you to the GCAN collaborators, as well as Drs. Laura M. Thornton, Patrick F. Sullivan, and Eleftheria Zeggini for their contributions. Thank you to the Canadian Institutes of Health Research for funding me throughout my graduate studies, Centre for Addiction and Mental Health/Government of Ontario AHSC AFP Innovation Fund and Ontario Mental Health Foundation for their grant support. I would also like to thank all the patients, without whom this research would not be possible. iv Members of the Neurogenetics Laboratory, Clinical Research Department, and Institute of Medical Science (IMS) have been a great source of support throughout my PhD. I would like to thank the postdoctoral fellows who made this work possible and for showing me how to be a scientist with integrity: Dr. Clement Zai for being a brilliant mentor and teaching me everything I know about genetic analysis, Dr. Arun Tiwari for always making time for me and his tremendous help with the selection of functional markers, and Dr. Vanessa Gonçalves for her support, inspiration, and opening my eyes to new research horizons. I would also like to acknowledge the following present or past members of the Neurogenetics Lab for their assistance and support: Nabilah Chowdhury, Sarah Gagliano, Sajid Shaikh, Natalie Freeman, Dr. Renan Souza, Ryan Tong, Daniel Felsky, Matthew Lau, Dr. Vincenzo de Luca, Maria Tampakeras, Olga Likhodi, David Sibony, and David Irwin. Thank you to my clinical manager Susan Dickens, as well as to Andrea Smart, Mary Smirniw, and Jinoos Sotodeh for administrative assistance. I am grateful for the support of current and past IMS staff: Hazel Pollard, Kamila Lear, Dianne Fukunaga, Kaki Narh, Marika Galadza, Michelle Rosen, Elena Gessas, Rejeanne Puran, and Sezen Mert, as well as current and past IMS graduate coordinators: Drs. Mary Seeman, Howard Mount, Vasundara Venkateswaran, Cindi Morshead. Mingyao Liu, and Karen Davis. Many thanks to Laura Mackew and Michael Verdirame for volunteering their time to assist me with literature searches. On a personal note, I am thankful for the unwavering friendship and endless support of Akshita Kapila Vincent, Alan Liang, Sara Piran, and Shahad Abdulnour. Thank you to the members of Yilmaz, Turgut, and Walhelm families. Last but definitely not least, I would like to thank my father Nurettin Yilmaz, my mother Gulsen Yilmaz (née Turgut), my spouse Antti Walhelm, and my late grandmother Sidika Turgut for their unconditional love, encouragement, sacrifices, support, and faith in my abilities. To them I dedicate this work. v Table of Contents Chapter Section Title Page Abstract .................................................................................................................... ii Acknowledgements ................................................................................................. iv Table of Contents ..................................................................................................... vi List of Abbreviations ............................................................................................... x List of Tables ........................................................................................................... xiv List of Figures .......................................................................................................... xvi List of Appendices.................................................................................................... xvii 1 INTRODUCTION............................................................................................. 1 1.1. Individual, Collective, and Financial Burden of Anorexia Nervosa and Bulimia Nervosa ................................................................................ 1 1.2. Diagnostic Criteria for AN and BN ......................................................... 3 1.2.1. DSM-IV Criteria for AN ............................................................................ 5 1.2.2. DSM-IV Criteria for BN ............................................................................. 5 1.3. Clinical Phenotypes Associated with AN and BN .................................. 6 1.3.1. Depression and Anxiety .............................................................................. 6 1.3.2. Substance Use/Abuse ................................................................................. 8 1.3.3. Personality and Temperament .................................................................... 8 1.3.4. Attention-Deficit/Hyperactivity Disorder.................................................... 9 1.4. Epidemiology of AN and BN ................................................................... 10 1.5. Outcome of AN and BN ........................................................................... 11 1.6. The Current State of Psychiatric Genetics ............................................. 13 1.7. Genetics of AN and BN ............................................................................ 16 1.7.1. Heritability .................................................................................................. 17 1.7.2. Linkage Studies .......................................................................................... 18 1.7.3. Serotonin System Genes ............................................................................. 20 1.7.4. Other Gene Systems ................................................................................... 22 vi Chapter Section Title Page 1.7.5. GWAS ........................................................................................................ 24 1.8. Genetics of Appetite and Weight Regulation ......................................... 25 1.8.1. A Summary on the Heritability of Body Weight .......................................
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