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Investigation of Genetic and Molecular Susceptibility Factors for Bipolar Disorder

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Investigation of Genetic and Molecular Susceptibility Factors for Bipolar Disorder Investigation of genetic and molecular susceptibility factors for bipolar disorder Cristiana Cruceanu Department of Human Genetics Faculty of Medicine McGill University, Montreal, Canada March 2016 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © Copyright Cristiana Cruceanu 2016 1 Table of contents TABLE OF CONTENTS --------------------------------------------------------------------------------------------------------------------------------- 2 ABSTRACT/RESUME ---------------------------------------------------------------------------------------------------------------------------------- 3 ACKNOWLEDGEMENTS ------------------------------------------------------------------------------------------------------------------------------ 5 LIST OF ABBREVIATIONS----------------------------------------------------------------------------------------------------------------------------- 7 LIST OF FIGURES ------------------------------------------------------------------------------------------------------------------------------------- 12 LIST OF TABLES --------------------------------------------------------------------------------------------------------------------------------------- 13 PREFACE ------------------------------------------------------------------------------------------------------------------------------------------------ 14 CONTRIBUTION OF AUTHORS ---------------------------------------------------------------------------------------------------------------------------------------------- 14 ORIGINAL CONTRIBUTION TO KNOWLEDGE ------------------------------------------------------------------------------------------------------------------------------- 16 CHAPTER 1: INTRODUCTION --------------------------------------------------------------------------------------------------------------------- 18 PART 1.1: PREFACE -------------------------------------------------------------------------------------------------------------------------------------------------------- 18 PART 1.2: RESPONSE TO TREATMENT IN BIPOLAR DISORDER: RECENT MOLECULAR AND GENETIC FINDINGS --------------------------------------------------------- 19 PART 1.3: GENOME-WIDE APPROACHES IN BIPOLAR DISORDER IN THE ERA OF HIGH-THROUGHPUT SEQUENCING -------------------------------------------------- 31 PART 1.4: RATIONALE AND HYPOTHESES --------------------------------------------------------------------------------------------------------------------------------- 41 PART 1.5: OBJECTIVES ----------------------------------------------------------------------------------------------------------------------------------------------------- 42 CHAPTER 2: HIGH-THROUGHPUT APPROACHES TO IDENTIFY BD SUSCEPTIBILITY ---------------------------------------------- 44 PART 2.1 PREFACE --------------------------------------------------------------------------------------------------------------------------------------------------------- 45 PART 2.2: RARE SUSCEPTIBILITY VARIANTS FOR BIPOLAR DISORDER SUGGEST A ROLE FOR G PROTEIN-COUPLED RECEPTORS --------------------------------------- 48 PART 2.3: TRANSCRIPTOME SEQUENCING OF THE ANTERIOR CINGULATE IN BIPOLAR DISORDER: DYSREGULATION OF G PROTEIN-COUPLED RECEPTORS --------- 85 CHAPTER 3: CANDIDATE GENE STUDIES ---------------------------------------------------------------------------------------------------- 106 PART 3.1: PREFACE ------------------------------------------------------------------------------------------------------------------------------------------------------ 107 PART 3.2: SYNAPSIN II IS INVOLVED IN THE MOLECULAR PATHWAY OF LITHIUM TREATMENT IN BIPOLAR DISORDER ---------------------------------------------- 109 PART 3.3: H3K4 TRI-METHYLATION IN SYNAPSIN GENES LEADS TO DIFFERENT EXPRESSION PATTERNS IN BIPOLAR DISORDER AND MAJOR DEPRESSION ------- 126 PART 3.4: EPIGENETIC REGULATION OF SYNAPSIN GENES IN MOOD DISORDERS ------------------------------------------------------------------------------------- 144 CHAPTER 4: DISCUSSION ------------------------------------------------------------------------------------------------------------------------ 149 PART 4.1: DISCUSSION OF RESULTS AND IMPLICATIONS --------------------------------------------------------------------------------------------------------------- 150 PART 4.2: CONCLUSIONS AND FUTURE DIRECTIONS ------------------------------------------------------------------------------------------------------------------- 160 APPENDICES ----------------------------------------------------------------------------------------------------------------------------------------- 161 APPENDIX 1: SIGNIFICANT CONTRIBUTIONS BY THE THESIS AUTHOR TO OTHER PROJECTS --------------------------------------------------------------------------- 161 APPENDIX 2: SUPPLEMENTAL MATERIAL: “RARE SUSCEPTIBILITY VARIANTS FOR BIPOLAR DISORDER SUGGEST A ROLE FOR G PROTEIN-COUPLED RECEPTORS” 164 APPENDIX 3: SUPPLEMENTAL MATERIAL: “TRANSCRIPTOME SEQUENCING OF THE ANTERIOR CINGULATE IN BIPOLAR DISORDER: DYSREGULATION OF G PROTEIN-COUPLED RECEPTORS” ---------------------------------------------------------------------------------------------------------------------------------------- 197 APPENDIX 4: SUPPLEMENTAL MATERIAL: “H3K4 TRI-METHYLATION IN SYNAPSIN GENES LEADS TO DIFFERENT EXPRESSION PATTERNS IN BIPOLAR DISORDER AND MAJOR DEPRESSION” ----------------------------------------------------------------------------------------------------------------------------------------------- 217 BIBLIOGRAPHY ------------------------------------------------------------------------------------------------------------------------------------- 220 2 Abstract/Resume Abstract Bipolar disorder (BD) is a psychiatric condition characterized by at least two episodes of clinically significantly disturbed mood, energy, and activity. Given its debilitating nature, lifetime prevalence and significant occurrence in the general population (1-2.5%), BD is a major public health concern. We know that both environmental and genetic factors contribute to BD susceptibility, with a relatively high contribution of heritable factors (estimates ranging from 60 to 85%). In spite of the strong support for the role of genetics in BD, molecular studies have had little success in replicating specific gene findings, likely as a result of phenotypic and genetic heterogeneity. Alterations in gene expression and regulatory mechanisms in the brain have been shown to play a role in BD. To date, most of the findings point to broad dysregulation across many pathways that are essential for brain function. Questions remain about dysregulation of the plethora of non-coding transcripts whose importance in brain biology has been recently demonstrated, but not characterized for BD. The approaches used in the studies that comprise this thesis were designed to shed light on some of the susceptibility factors for BD, as well as to follow-up on previously implicated pathways and regulatory systems. Thus, high-throughput genome-wide exploratory investigations including whole exome sequencing and transcriptome sequencing, as well as hypothesis-driven candidate gene studies and manipulations of in vitro systems were included in this body of work. One major finding is the role of G protein-coupled receptors (GPCRs), both at the genomic level through an enrichment of deleterious mutations carried by affected individuals in the genes encoding these receptors, as well as through a global dysregulation of RNA expression of these receptors in the BD brain. A second major finding is a role for synaptic genes, particularly Synapsin II (SYN2), in BD susceptibility and response to treatment with the classical mood stabilizer drug lithium. The results presented in this thesis represent significant contributions toward characterizing the BD susceptibility profile, and shed light on genetic, transcriptional, and epigenetic mechanisms for disease etiology, causality, and course of illness. 3 Résume Les troubles bipolaires (TB) sont des troubles psychiatriques caractérisés par au moins deux épisodes où l’humeur, l’activité et l’énergie des patients sont cliniquement perturbés. Dû a sa nature débilitante et sa forte prévalence dans la population générale (1-2,5%), les TB sont des problèmes majeurs de santé publique. Des facteurs génétiques et environnementaux sont impliqués dans l’étiologie des TB, avec notamment une forte contribution de facteurs héréditaires (estimations allant de 60 à 85%). Malgré l’importance du déterminisme génétique dans la susceptibilité aux TB, les résultats des études gènes candidats ont été très peu répliqués, probablement à cause de l'hétérogénéité phénotypique et génétique, et de l’hérédité complexe des troubles. Des modifications de l'expression des gènes et des mécanismes de régulation dans le cerveau jouent également un rôle dans les TB. Aujourd’hui, la plupart des résultats pointent vers des dérèglements majeurs dans de nombreux mécanismes qui sont essentiels pour le fonctionnement du cerveau. Des questions demeurent sur la régulation d’un grand nombre de transcrits non codants (dont l'importance a été récemment démontré dans la biologie du cerveau) et sur la caractérisation de ces mécanismes dans les TB. Les approches utilisées dans mes travaux de thèse ont été conçues à la fois pour mettre en lumière des facteurs de susceptibilité aux TB, et pour caractériser plus finement des voies biologiques et des systèmes de régulations. Pour ce faire, des études haut
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