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Genetics of Obsessive-Compulsive Disorder: from Phenotypes to Pharmacogenetics

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GENETICS OF OBSESSIVE-COMPULSIVE DISORDER: FROM PHENOTYPES TO PHARMACOGENETICS by Gwyneth Ching Mung Zai A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Gwyneth Ching Mung Zai 2016 Thesis Title: Genetics of Obsessive-Compulsive Disorder: From Phenotypes to Pharmacogenetics Name: Gwyneth Ching Mung Zai Degree: Doctor of Philosophy Department: Institute of Medical Science Institution: University of Toronto Year of Convocation: 2016 Overall Abstract Background: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder that is characterized by a diverse clinical presentation. Evidence suggests genetic involvement in the etiology of OCD; however, genetic association studies have yielded mixed results partly due to clinical heterogeneity. Aims: We therefore investigated the genetics of OCD subphenotypes: age at onset (AAO), Yale- Brown Obsessive-Compulsive Scale (Y-BOCS) severity score and symptom dimensions, family history of obsessive-compulsive and related disorders (OCRDs), psychiatric comorbidities, and drug response. We first examined these subphenotypes to ascertain clinically homogeneous dimensions of OCD. We then analyzed these subphenotypes and antidepressant response for genetic association to identify marker(s) for each subphenotype. Methods: The sample consists of 560 OCD individuals. For the subphenotypic analyses, admixture analysis (STATA) was performed to analyze AAO and factor analysis (SPSS) was applied to reduce the Y-BOCS symptom checklist. Family history and psychiatric comorbidity ii were obtained using the modified Family History Index and SCID-IV interviews respectively. The candidate gene study investigated markers, mostly in the remote regulatory regions, of 17 candidates for association with subphenotypes in 497 OCD participants. Genome-wide association study was conducted in a subset of this sample to examine AAO and Y-BOCS severity. Retrospective antidepressant response data was available in 222 OCD individuals. Statistical analyses were performed using SPSS, PLINK, and R programs, comparing genotype frequencies between different subphenotype groups. Results: We identified early (≤8), intermediate (9-17), and late onset (≥18 years) OCD groups, and a 5- or 6-factor model by weighing Y-BOCS symptoms. Our sample revealed the following clinical differences: females had a higher percentage of comorbid lifetime OCRDs and the early onset group was associated with greater symmetry/order and contamination/cleaning symptoms. However, our genetic studies revealed no significant findings across all OCD subphenotypes and antidepressant response after correction for multiple comparisons. Conclusions: Interesting results, although negative, suggest the role of serotonergic and glutamatergic system genes in addition to a newly identified candidate in influencing OCD subphenotypes and antidepressant response. Although replication studies are warranted, these results contribute to the future development of genetic tests to assess for OCD risk and antidepressant response, leading to better outcome for OCD patients. Word Count: 350 iii Acknowledgments I would like to give my special and sincere thanks to my family, especially my parents, Mr. Henry and Mrs. Elizabeth Zai, my brothers, Dr. Clement Zai and Mr. Felix Zai, and my fiancé, Mr. Sunny Chan, my friends and colleagues from medical school and psychiatry residency, my clinical and research supervisors and mentors for their tremendous help and support throughout my Ph.D. study. I dedicate this Ph.D. thesis to them. Regarding research, I would like to especially thank my supervisors and mentors, Dr. James L. Kennedy and Dr. Margaret (Peggy) A. Richter, for their guidance, teaching, and insightful comments on my projects as well as advice on my future career path. I would like to express my gratitude to my international mentors (Dr. Katharine Phillips, Dr. Matthew Rudorfer, and Dr. Mark Vawter) and research supervisors (Dr. David Pauls, Professor Barbara Sahakian, and Professor Trevor W. Robbins) for their time, guidance, and support. I would also like to thank the members of my Ph.D. advisory committee, Dr. Joanne Knight and Dr. Paul Arnold, final PAC external advisor, Dr. Paul Sandor, and other members of my Ph.D. examination committee, Dr. Mary Seeman, and Dr. Daniel Geller. For the peer-reviewed process of the original article chapters of this thesis, I would like to thank Dr. Blair Simpson, Dr. Don Black, Dr. Lea Davis, and Dr. Dan Rujescu for their time and constructive feedback. Within the Institute of Medical Science, I would like to acknowledge the director, graduate coordinators, and administrative staff for their hard work and support. For the research team, many thanks to all members of the Psychiatric Neurogenetics Laboratory (Dr. Kennedy’s lab) at the Centre for Addiction and Mental Health (lab manager – Ms. Natalie Freeman; IMPACT study manager – Ms. Nicole Braganza; IMPACT study research analyst – Mr. Sheraz Cheema; lab technicians – Mr. Sajid Shaikh, Mr. David Sibony, and Ms. Maria Tampakeras; visiting postdoctoral fellows – Dr. Vanessa Gonçalves and Dr. Arun Tiwari; colleagues – Dr. Vincenzo de Luca and Dr. Daniel Mueller), the CAMH scientific computing team (manager – Mr. David Rotenberg), and the Frederick W. Thompson Anxiety Disorders Centre at the Sunnybrook Health Sciences Centre (research assistant – Ms. Marissa Williams; database manager – Ms. Karen Wigg; therapist – Ms. Eliza Burroughs; administrative staff – Ms. Carmen Costa and Ms. Amanda Calzolaio), for making my doctoral experience stimulating and exciting. I would further like to acknowledge iv my international collaborators (Brazil: Dr. Roseli Shavitt, Dr. Euripedes Miguel, Dr. Carolina Cappi, and Dr. Maria Conceição do Rosario; USA: Dr. Carol Mathews, Dr. Gregory Hanna, Dr. Thomas Fernandez, Dr. Lea Davis, Dr. James Knowles, and Dr. Dongmei Yu; Spain: Dr. Pino Alonso and Dr. Xavier Estivill; Netherlands: Dr. Danielle Cath and Dr. Eske Derks; Italy: Dr. Cristina Cavallini; Switzerland: Dr. Edna Grünblatt and Dr. Susanne Walitza; South Africa: Dr. Dan Stein and Dr. Christine Lochner; Mexico: Dr. Humberto Nicolini; Canada: Dr. Evelyn Stewart; UK: Professor Naomi Fineberg, Dr. Sam Chamberlain, Dr. Becky Inkster, Dr. Annette Brühl, Dr. Annemieke Apergis-Schoute, Dr. Sharon Morein-Zamir, and Ms. Matilde Vaghi) and their administrative staff for their contributions in my career development and Ph.D. thesis. Finally, I would like to give my sincere thanks and gratitude to all research participants for their time and effort. Regarding funding, I would like to acknowledge the Ontario Ministry of Health and Long-Term Care (PGY-5 residency salary from 2012-2014), the Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship (salary from 2014-2016), the W. Garfield Weston Doctoral Fellowship (fellowship travel expense and salary from 2014-2015), the Younger Foundation (conference allowance in 2014) and the Frederick W. Thompson Anxiety Disorders Centre (travel allowance in 2014-2015) for supporting my salary, research allowance, and/or conference expenses. Research funding was supported by a grant from the Ontario Mental Health Foundation (Drs. Richter and Kennedy) and a private donation from the Frederick W. Thompson family (Dr. Richter). v Contributions Chapter 1: Dr. Gwyneth Zai conducted a thorough literature search on the genetics of obsessive- compulsive disorder (OCD) phenotypes and pharmacogenetics, and she completed the entire chapter. A large part of this chapter was taken from a recent review on the pharmacogenetics of OCD, for which Dr. Gwyneth Zai is the first author, and she performed a thorough literature search and review, wrote, submitted, and revised the manuscript for publication. This review article has been published in the journal of Pharmacogenomics 2014; 15(8):1147-1157. Chapter 2: Dr. Gwyneth Zai designed the aims, objectives, and hypothese (with guidance from faculty) for this PhD thesis. Chapter 3: Dr. Gwyneth Zai designed the experiment (with guidance from faculty), performed data collection, corresponded with co-authors, performed all statistical analyses, wrote and revised the manuscript, which is ready for publication. Chapter 4: Dr. Gwyneth Zai designed the experiment (with guidance from faculty), performed part of the data collection and all genotyping, corresponded with co-authors, performed all the statistical analyses, wrote and revised the manuscript, which is ready for publication after the completion of replication study. Chapter 5: Dr. Gwyneth Zai designed the experiment (with guidance from faculty), performed part of the data collection, corresponded with co-authors, performed all the statistical analyses, wrote and revised the manuscript, which is ready for publication after the completion of replication study. Chapter 6: Dr. Gwyneth Zai designed the experiment (with guidance from faculty), performed data collection and most of the genotyping, corresponded with co-authors, performed all the statistical analyses, wrote and revised the manuscript, which is ready for publication after replication study. Chapter 7: Dr. Gwyneth Zai wrote the entire final chapter, summarizing the results, and providing limitations and future directions to extend the findings from the PhD thesis. vi Table of Contents Acknowledgments .........................................................................................................................
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