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Genetic Association Studies of Bipolar Disorder

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Genetic Association Studies of Bipolar Disorder Genetic Association Studies of Bipolar Disorder Dr Nicholas James Bass This thesis is submitted for the degree of Doctor of Medicine (MD) at University College London 2007 Molecular Psychiatry Laboratory Department of Mental Health Sciences Royal Free and University College London Medical School The Windeyer Institute of Medical Sciences 46 Cleveland Street London W 1T4JF 1 UMI Number: U591560 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U591560 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Statement of Conjoint Work My work was very much part of a team effort. My specific contributions were: 1. UCL bipolar sample collection - recruitment, diagnostic interviewing, blood sampling and data management of 300 bipolar volunteers and over 100 control volunteers. 2. DNA preparation - extraction, quantification and plating out for PCR-based analysis. 3. Marker selection - from literature and using bioinformatic tools. 4. Microsatellite genotyping at BDNF, P2RX7 and COMT loci. 5. Microsatellite genotyping at DISCI locus in conjunction with Cindy Yang. 6. SNP genotyping at BDNF and COMT loci using Taqman, Amplifluor and RFLP assays. 7. Statistical analysis of data. Dr Cindy Yang presented some of the microsatellite data relating to the DISCI locus in her MSc (Molecular Medicine) thesis 2005. O 8/c'i /cy 2 Abstract Bipolar disorder is a common and serious mental illness. The occurrence of mania is central to the diagnosis, but affected individuals typically also suffer episodes of depression. The results of family, twin and adoption studies argue convincingly for genetic susceptibility to bipolar disorder. Linkage studies conducted at the Molecular Psychiatry Laboratory, UCL have previously implicated the regions 12q24, 21q22, lq42 and 11 p 14- 15 as harbouring susceptibly loci for bipolar disorder. In this thesis I report fine mapping of the 12q24, 21q22 and lq42 regions by linkage disequilibrium methods, employing a case-control design. For the llpl4-15 region association with the candidate gene BDNF was tested. I also present attempts to replicate findings of association at the genes DAOA and COMT, located in regions implicated by meta-analysis of the linkage data. I have attempted to put these investigations in context, necessitating consideration of the conceptual developmental of bipolar disorder, the classical techniques for assessing the genetic contribution to aetiology, and mapping strategies. Fine mapping of the UCL linkage regions implicated two novel susceptibility loci and provided support for two previously identified loci. Association of multiple markers within a 180 kb region of 12q24.3 was found, implicating Slynar and LOC387895. Association was also found with two markers in the more centromeric gene P2RX7, previously implicated in a Canadian sample. Multiple associated markers were found on 21q22.3. Two candidate genes - C21orf29 and TRPM2 - were identified from this region. Initial efforts to fine map the lq42 region suggested the involvement of the previously implicated DISCI gene. However association was only found with a single marker. Although haplotypic association was found with BDNF, the complex structure of the microsatellite marker hindered interpretation of the results. Partial replication of the association with DAOA was achieved but the involvement of COMT was not supported. 3 Contents Acknowledgements ...................................................................................................................... ..9 Chapter 1: What is Bipolar Disorder?............................................................................... 10 1.1 Modem conceptualisation .................................................................................................. 10 1.2 Clinical aspects .................................................................................................................... 14 1.3 Is bipolar disorder im portant? ........................................................................................... 15 1.4 Is bipolar disorder treatable? ............................................................................................. 17 1.5 Historical perspective .......................................................................................................... 20 1.6 Sum m ary............................................................................................................................... 24 Chapter 2: Is Bipolar Disorder Genetic?........................................................................... 26 2.1 The problem of phenotype definition .............................................................................. 26 2.2 Evidence for genetic aetiology to bipolar disorder ....................................................... 28 2.2.1 Family studies................................................................................................................ 29 2.2.2 Segregation analysis ..................................................................................................... 31 2.2.3 Twin studies ................................................................................................................... 35 2.2.4 Adoption studies ........................................................................................................... 39 2.3 Summary............................................................................................................................... 40 Chapter 3: Mapping Bipolar Disorder I - Chromosomal Aberrations and Linkage Analysis.................................................................................................................................. 42 3.1 Methods of gene mapping ................................................................................................. 42 3.2 Chromosomal aberrations ................................................................................................. 43 3.3 Linkage .................................................................................................................................. 45 3.3.1 Basic concept ................................................................................................................ 45 3.3.2 Parametric and non-parametric analysis ................................................................... 46 3.3.3 M arkers........................................................................................................................... 48 3.3.4 Linkage findings in bipolar disorder ......................................................................... 49 3.3.5 Review of meta-analyses of bipolar linkage studies .............................................. 53 3.3.6 Homozygosity mapping .............................................................................................. 58 3.4 Summary.............................................................................................................................. 59 Chapter 4: Mapping Bipolar Disorder II - Linkage Disequilibrium Mapping ......... 61 4.1 Basic concept ........................................................................................................................ 61 4.2 LD measures......................................................................................................................... 63 4.3 Study design ......................................................................................................................... 64 4.3.1 Power ............................................................................................................................... 64 4.3.2 Sample groups ............................................................................................................... 66 4.3.3 Populations .................................................................................................................... 68 4.3.4 Markers........................................................................................................................... 69 4.3.5 Haplotype analysis ....................................................................................................... 70 4.3.6 Statistical considerations ............................................................................................. 72 4.3.7 Systematic LD mapping versus candidate gene approach .................................... 73 4.4 Association studies in bipolar disorder ........................................................................... 74 4.4.1 Meta-analysis of association studies ......................................................................... 75 4.4.2 Meta-analysis of 5-HTT association ......................................................................... 76 4.4.3 Meta-analysis of MAO A association ........................................................................ 81 4.4.4 Interpretation of meta-analysis .................................................................................. 84 4 4.5 Genomewide
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