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Bipolar Disorder Related Functional Variants in the Calcium Channel Gene Family

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Bipolar Disorder Related Functional Variants in the Calcium Channel Gene Family Bipolar Disorder Related Functional Variants in the Calcium Channel Gene Family. Niamh Louise O’Brien Division of Psychiatry University College London, Thesis submitted for the degree of Doctor of Philosophy UCL 1 I, Niamh O’Brien confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Bipolar disorder (BD) is a common highly heritable disorder. The calcium channel gene family has been widely implicated in BD aetiology and these genes include CACNA1C, and CACNG4. The association signal for CACNA1C with BD is located in the middle of the third intron of the gene. CACNG4 encodes a transmembrane AMPA receptor regulator that is involved in trafficking AMPA receptors to the neuronal post-synaptic density. High-resolution melting curve (HRM) analysis and whole genome sequencing (WGS) methods were used to identify functional variants in calcium channels genes in the UCL BD cohort. Variants that were predicted to impact gene regulation, transcription or to be damaging to protein structure were genotyped in the larger UCL BD and control cohort. HRM analysis identified 26 calcium channel gene variants. These included two non-synonymous CACNG4 variants that were associated with mental illness (rs371128228, p=1.05x10-4, OR=4.39 and 17:65026851 (C/T), p=5x10-4, OR=9.52). Fluorescent activated cell sorting analysis was used to determine the effect of rs371128228 on trafficking of GluR1 and GluR2 to the cell surface. This analysis demonstrated that the risk allele of rs371128228 significantly decreased cell surface trafficking of GluR1 (p=0.026) but no effect was observed on GluR2 trafficking. WGS analysis of CACNA1C intron 3 identified two BD associated (p=0.015, OR=1.15) variants 105bp apart that were in complete LD. Both variants are predicted to create YY1 transcription factor binding sites. Luciferase reporter assays show a significant decrease in gene expression in the presence of both variants (p=0.004). Protein-DNA complex assays of the CACNA1C variants demonstrate increased nuclear proteins binding affinity for the variant alleles. If these calcium channel variants are confirmed to be important risk factors for BD they could be used as markers for personalised treatment or in the identification of genetic subtypes of BD or other psychiatric illness. 3 Acknowledgements As the end of my time working on this thesis draws to a close I am very aware of the amount of support and direction I have received over the course of my PhD. First and foremost I would like to thank my supervisor Dr.Andrew McQuillin for giving me the wonderful opportunity to carry out this work and PhD and for all of his advice and support throughout the years, no matter how silly the questions I may have asked were. I would like to thank Dr. Hugh Gurling for his introduction to the Molecular Psychiatry laboratory and support and advice during the first years of my PhD. I would like to extend my sincerest gratitude to Dr. Nicholas Bass, who after Dr. Gurling sadly passed away took over the mantle as my secondary supervisor and continued to support me through my PhD. Dr.Bass’s advice and feedback during my write up and constant source of encouragement to keep going was invaluable. My sincerest thanks go to The Bipolar Foundation: Equilibrium and the Fairclough family for providing the funding which has given me the opportunity to work in a field of great interest to me over the course of my PhD. Without this I would not have been able to work in the field of psychiatric genetics. The next in line are my parents and family who have given me tremendous support throughout the course of my work. I can never thank them enough for the encouragement and motivation following my move to London and during the last number of years. They have always pushed me to strive for the best and have listened to me talk about my work non-stop, even when they may not have understood anything I was saying. A very special thanks needs to go to both Alessia and Sally. Without their help I would not be the researcher I am today. They were always on hand no matter how small or large the questions I had about science were. I am greatly indebted to them for their support, advice and friendship during this time. I would like to thank all of my current and ex-colleagues of the Molecular Psychiatry lab, Michael, Yi, Jon, Alex, Kate, Giorgia and Mariam for their support. 4 I would like to thank everyone, especially Kleoniki, Chris, Jaspal and Niamh, who has listened to me complain about failed experiments and thesis writing. There have been many times when your friendship, support and ability to make me laugh have been the exact remedy I needed and you have never shown exasperation whether you felt it or not. A special thanks to Chris as well for helping me with the enormous task of proof-reading this thesis. Last but not least I am sincerely grateful to my partner Gavriil for his constant and never ending support during my PhD. I would like to thank him for his cool calm attitude, his constant emotional support and motivation, the late night food runs and for never doubting my abilities. Lastly, I would like to thank everyone again who has made this possible and made the journey extremely memorable and enjoyable. 5 Table of Contents ABSTRACT 3 ACKNOWLEDGEMENTS 4 TABLE OF CONTENTS 6 LIST OF FIGURES 10 LIST OF TABLES 13 LIST OF ABBREVIATIONS 16 CHAPTER 1 INTRODUCTION 21 1.1 BIPOLAR DISORDER 21 1.1.1 OVERVIEW 21 1.1.2 HISTORY AND CLASSIFICATION 24 1.1.3 DIAGNOSTIC CRITERIA 26 1.1.4 BIPOLAR DISORDER SUBTYPES 30 1.1.5 BIOCHEMICAL PATHWAYS IMPLICATED IN BIPOLAR DISORDER 36 1.1.6 TREATMENT OF BIPOLAR DISORDER 40 1.2 GENETICS OF BIPOLAR DISORDER 46 1.2.1 HERITABILITY OF BIPOLAR DISORDER 46 1.2.2 MOLECULAR GENETIC STUDIES OF BIPOLAR DISORDER 50 1.3 CALCIUM CHANNEL GENES 81 1.3.1 INTRODUCTION 81 1.3.2 GENETIC VARIATION IN CALCIUM CHANNEL GENES 95 1.4 INTRONIC GENETIC VARIATION 99 1.4.1 INTRODUCTION 99 1.4.2 ENCODE DATA 100 1.4.3 UTILISING DATA SETS SUCH AS ENCODE TO INVESTIGATE NGS 103 CHAPTER 2 AIMS OF THESIS 104 CHAPTER 3 MATERIAL AND METHODS 105 3.1 GENERAL METHODS 105 3.1.1 UCL RESEARCH SUBJECTS 105 3.1.2 GENOMIC DNA EXTRACTIONS 107 3.1.3 DNA QUANTIFICATIONS 110 6 3.1.4 POLYMERASE CHAIN REACTION 111 3.1.5 AGAROSE GEL ELECTROPHORESIS 114 3.1.6 MAMMALIAN CELL CULTURE 116 3.2 METHODS FOR RESULTS CHAPTER 4 AND 5: HIGH-RESOLUTION MELTING CURVE ANALYSIS IN CALCIUM CHANNEL GENES 120 3.2.1 RESEARCH SAMPLES 120 3.2.2 HIGH-RESOLUTION MELTING 120 3.2.3 PURIFICATION OF SAMPLES 121 3.2.4 SANGER SEQUENCING 123 3.2.5 VARIANT SELECTION FOR KASPAR GENOTYPING 126 3.2.6 SNV GENOTYPING WITH KASPAR 127 3.2.7 PLASMID CONSTRUCTION 133 3.2.8 CELLULAR TRANSFECTIONS 147 3.2.9 FLOW CYTOMETRY 147 3.3 METHODS FOR RESULTS CHAPTER 5: INVESTIGATION OF VARIANTS USING NEXT GENERATION SEQUENCING ANALYSIS 149 3.3.1 RESEARCH SAMPLES FOR NEXT GENERATION SEQUENCING 149 3.3.2 NEXT GENERATION SEQUENCING AND ANALYSIS 149 3.3.3 VARIANT SELECTION 151 3.3.4 KASPAR GENOTYPING 152 3.3.5 STATISTICAL ANALYSIS 152 3.3.6 PLASMID CONSTRUCTION 153 3.3.7 LUCIFERASE ASSAY 158 3.3.8 ELECTROMOBILITY SHIFT ASSAY 160 3.3.9 EMSA SUPERSHIFT ASSAY 164 CHAPTER 4 HIGH-RESOLUTION MELTING CURVE ANALYSIS OF REGULATORY REGIONS IN CALCIUM CHANNEL GENES 165 4.1 INTRODUCTION 165 4.2 HYPOTHESIS 169 4.3 AIMS 169 4.4 HRM METHODS FOR SCREENING CACNA1C, CACNA1D, AND CACNB3 170 4.5 RESULTS 171 4.5.1 HRM SCREENING OF GENES 171 4.5.2 INVESTIGATION OF THE EFFECTS OF VARIANTS 172 4.5.3 GENOTYPING OF VARIANTS FROM HRM 175 4.6 DISCUSSION 176 7 CHAPTER 5 HIGH RESOLUTION MELTING CURVE ANALYSIS OF CACNG4 179 5.1 INTRODUCTION 179 5.2 HYPOTHESIS 181 5.3 AIMS 183 5.4 HRM SCREENING OF CACNG4 183 5.5 RESULTS 185 5.5.1 HRM SCREENING OF GENES 185 5.5.2 INVESTIGATION OF VARIANT EFFECTS 185 5.5.3 GENOTYPING OF VARIANTS DETECTED BY HRM 187 5.5.4 EFFECT OF RS371128228 ON AMPA-R TRAFFICKING 193 5.6 DISCUSSION 198 CHAPTER 6 INVESTIGATION OF VARIANTS IN CALCIUM CHANNEL GENES USING NEXT GENERATION SEQUENCING DATA 205 6.1 EXONIC REGIONS 205 6.1.1 INTRODUCTION 205 6.1.2 HYPOTHESIS 206 6.1.3 AIM 206 6.1.4 RESULTS 206 6.1.5 DISCUSSION 213 6.2 INTRONIC VARIANTS 215 6.2.1 INTRODUCTION 215 6.2.2 AIMS 217 6.2.3 HYPOTHESIS 217 6.2.4 RESULTS 218 6.2.5 DISCUSSION 237 CHAPTER 7 GENERAL DISCUSSION 241 7.1 STUDY LIMITATIONS AND POTENTIAL CONFOUNDS 245 7.2 FUTURE DIRECTIONS 246 REFERENCES 248 APPENDIX I 274 APPENDIX II 281 II.I DNA EXTRACTION FROM BLOOD SAMPLES 281 II.II AGROSE GELS 281 II.III CELL CULTURE 282 8 II.IV TRANSIENT TRANSFECTION 282 II.V PURIFICATION OF PCR PRODUCTS 282 II.VI MINI AND MIDI PREP 283 II.VII EMSA 283 APPENDIX III 285 APPENDIX IV 288 PUBLICATIONS 290 9 List of Figures Figure 1. Common symptoms of Bipolar Disorder. .............................................................. 23 Figure 2. Weighted mean for discharge diagnoses in 6 psychiatric treatment centres in the United States between 1972-1988................................................................
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