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Serotonin Genes and Their Association with OC Trait ‘Long’ Story ‘Short’: Serotonin Genes and Their Association with OC Trait Dimensions and Hoarding in a Community, Pediatric Sample and with Brain Volume Differences in a Clinical, Pediatric OCD Sample by Vanessa M. Sinopoli A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy (PhD) Institute of Medical Science, Faculty of Medicine School of Graduate Studies University of Toronto © Copyright by Vanessa M. Sinopoli (2019) ‘Long’ Story ‘Short’: Serotonin Genes and Their Association with OC Trait Dimensions and Hoarding in a Community, Pediatric Sample and with Brain Volume Differences in a Clinical, Pediatric OCD Sample Vanessa M. Sinopoli Doctor of Philosophy (PhD) Institute of Medical Science, Faculty of Medicine School of Graduate Studies University of Toronto 2019 ABSTRACT Background: Serotonin genes are commonly studied in obsessive-compulsive disorder (OCD), but findings have been inconsistent. OCD is phenotypically heterogeneous, with subgroups reflecting symptom dimensions, sex, and age of onset. The thesis aimed to reduce heterogeneity in pediatric samples, stratifying by sex and studying either homogenous symptom-based subgroups or studying structural brain imaging as putative intermediate OCD phenotypes. For Study 1, we hypothesized that different serotonin gene variants would be associated with different obsessive-compulsive (OC) trait dimensions. In Study 2, we examined hoarding traits more closely and hypothesized that unique serotonin gene variants would be associated with hoarding in the absence of other OC traits. For Study 3, we hypothesized that specific serotonin gene variants would differ in their relationship with regional brain volume between OCD patients and controls. ii Methods: We genotyped candidate serotonin genes in 5213 pediatric participants in the community (for Studies 1 and 2) and in 200 pediatric participants in the clinic (for Study 3). In Studies 1 and 2, we assessed the association between gene variants and trait groups in males and females separately. In Study 3, we conducted structural magnetic resonance imaging (sMRI) to measure regional brain volumes within cortico-striato-thalamo-cortical (CSTC) circuits. In males and females separately, we assessed the effect of genotype-diagnosis interaction on brain volume. Results: In Study 1, the [LG + S] variant in 5-HTTLPR was significantly associated with hoarding in males (P-value of 0.003). In Study 2, [LG + S] was significantly associated with hoarding alone in males (P-value of 0.009). In Study 3, there was a significant genotype- diagnosis interaction for two single nucleotide polymorphisms (SNPs) in HTR2C, rs12860460 (P-value of 9.70e-8) and rs12854485 (P-value of 2.07e-6) in females. Conclusions: Study 1 indicated that hoarding may be distinct in its underlying serotonin system genetics and Study 2 more specifically showed that hoarding traits alone were driving our findings in Study 1. Study 3 suggested that sequence variation in HTR2C influences ACC volume in female pediatric OCD. Future genetic association studies in OCD should similarly account for heterogeneity and study homogenous subgroups, where possible, to help further decipher the biological mechanisms driving symptoms. iii ACKNOWLEDGEMENTS Research Personnel, Supervisors, and Mentors: Dr. Paul Arnold (supervisor), Dr. Russell Schachar (Program Advisory Committee member), Dr. Peggy Richter (Program Advisory Committee member), Dr. Christie Burton (lab personnel and mentor) Other Individuals: My family, my husband, my son, and my close friends for their patience, support, and encouragement to persevere GENERAL STATEMENT OF CONTRIBUTIONS The following individuals have contributed to my published review and/or to at least one of my three studies as coauthors (research personnel, lab technicians, statisticians, colleagues, collaborators): Lauren Erdman, Christie L. Burton, Sefi Kronenberg, Laura S. Park, Rageen Rajendram, Julie Coste, Annie Dupuis, Janet Shan, Tara Goodale, S-M Shaheen, Jennifer Crosbie, Phillip Easter, Gregory Baldwin, Kelli Peterman, Gregory L. Hanna, David R. Rosenberg, Russell J. Schachar, Paul D. Arnold Funding: I received funding from the Canadian Institutes of Health Research (CIHR) Master's Award: Frederick Banting and Charles Best Canada Graduate Scholarships, Ontario Graduate Scholarship (OGS), and the Hospital for Sick Children Restracomp Studentship. iv Published Material: The LITERATURE REVIEW chapter is modified from the following article and contains the entire article contents, in full: Sinopoli, V. M., Burton, C. L., Kronenberg, S., & Arnold, P. D. (2017). A review of the role of serotonin system genes in obsessive-compulsive disorder. Neuroscience and Biobehavioral Reviews, 80, 372-381. The chapter, STUDY 1, is modified from the following article and contains the entire article contents, in full: Sinopoli, V. M., Erdman, L., Burton, C. L., Park, L. S., Dupuis, A., Shan, J., Goodale, T., Shaheen, S-M, Crosbie, J., Schachar, R. J., Arnold, P. D. (2019). Serotonin system genes and obsessive-compulsive trait dimensions in a population-based, pediatric sample: A genetic association study. Journal of Child Psychology and Psychiatry, doi: 10.1111/jcpp.13079. [Epub ahead of print] The chapter, STUDY 2, is modified from the following article and contains the entire article contents, in full: Sinopoli, V. M., Erdman, L., Burton, C. L., Park, L. S., Dupuis, A., Shan, J., Goodale, T., Shaheen, S-M, Crosbie, J., Schachar, R. J., Arnold, P. D. (under review). Serotonin system genes and hoarding with and without other obsessive-compulsive traits in a population-based, pediatric sample: A genetic association study. Depression and Anxiety. The chapter, STUDY 3, is modified from the following article and contains the entire article contents, in full: Sinopoli, V. M., Erdman, L., Burton, C. L., Easter, P., Rajendram, R., Baldwin, G., Peterman, K., Coste, J., Shaheen, S-M, Hanna, G. L., Rosenberg, D. R., Arnold, P. D. (2019). Serotonin system gene variants and regional brain volume differences in pediatric OCD. Brain Imaging and Behavior, doi: 10.1007/s11682-019-00092-w. [Epub ahead of print] v TABLE OF CONTENTS Page 1. LITERATURE REVIEW.....................................................................................................1 1.1. Overview of obsessive-compulsive disorder (OCD).........................................................3 1.2. History of obsessive-compulsive phenomena....................................................................3 1.3. Diagnostic criteria...............................................................................................................5 1.3.1. OCD...................................................................................................................................6 1.3.2. Body dysmorPhic disorder (BDD)..................................................................................8 1.3.3. Hoarding disorder............................................................................................................9 1.3.4. Trichotillomania (hair-Pulling disorder).......................................................................9 1.3.5. Excoriation (skin-Picking) disorder.............................................................................10 1.4. Etiology of OCD: Differences in pediatric etiology.......................................................10 1.5. OCD and the serotonin system........................................................................................11 1.6. Discovery of serotonin......................................................................................................14 1.6.1. The function of serotonin as a neurotransmitter........................................................15 1.6.2. Discovery of serotonergic antidePressants...................................................................16 1.7. OCD treatment..................................................................................................................17 1.7.1. Pharmacotherapy...........................................................................................................17 1.7.2. Pharmacological mechanisms of SRIs.........................................................................18 1.7.3. Psychotherapy and other treatment.............................................................................19 1.8. A review of the role of serotonin system genes in OCD.................................................19 1.9. Candidate gene studies of serotonin system genes in OCD...........................................20 1.10. The serotonin transPorter gene (SLC6A4)....................................................................21 1.10.1. The serotonin transPorter-linked polymorPhic region (5-HTTLPR)......................22 vi 1.10.2. Variable number of tandem rePeats polymorPhism in intron 2 (STin2 VNTR) and other SLC6A4 variants................................................................24 1.11. SLC6A4: Genetic association with OCD.......................................................................24 1.11.1. 5-HTTLPR.....................................................................................................................24 1.11.2. STin2 VNTR and other SLC6A4 variants..................................................................25 1.12. Serotonin 2A recePtor gene (HTR2A): Genetic association with OCD......................27 1.13. Serotonin 1B recePtor gene (HTR1B): Genetic association with OCD......................28
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