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Studying Complex Traits in the Post-GWAS Era: Application to Asthma and Allergy-Related Traits

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Studying Complex Traits in the Post-GWAS Era: Application to Asthma and Allergy-Related Traits Studying complex traits in the post-GWAS era: application to asthma and allergy-related traits Andréanne Morin Department of Human Genetics Faculty of Medicine McGill University, Montreal, Canada August 2017 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © Andréanne Morin 2017 1 Table of Content Table of Content ..................................................................................................... 2 Abstract/Résumé ..................................................................................................... 4 Abstract ...................................................................................................................................... 4 Résumé ....................................................................................................................................... 5 Acknowledgements ................................................................................................. 7 List of Abbreviations .............................................................................................. 9 List of Figures ....................................................................................................... 14 List of Tables ......................................................................................................... 16 Preface ................................................................................................................... 17 Contribution of authors .......................................................................................................... 17 Original contribution to knowledge ...................................................................................... 19 Chapter 1: Introduction ....................................................................................... 21 1.1 Complex traits: asthma and allergic diseases as an example ........................................ 21 1.2 The Genome-Wide Association Study (GWAS) era ...................................................... 21 1.2.1 “Missing” or “hidden” heritability in complex traits ................................................... 24 1.3 Assessing functional impact of variants .......................................................................... 25 1.3.1 DNase I Hypersensitive sites (DHS) ............................................................................ 26 1.3.2 Linking SNPs to gene expression: expression Quantitative Trait Loci (eQTL) and Allele-Specific Expression (ASE) ........................................................................................ 26 1.3.3 Linking SNPs to DNA methylation: methylation Quantitative Trait Loci (mQTL) and Allele-Specific Methylation (ASM) ..................................................................................... 28 1.3.4 Rare variants and cellular traits .................................................................................... 29 1.4 Exploring rare and low-frequency variants in complex traits ...................................... 29 1.4.1 Custom Genotyping arrays .......................................................................................... 30 1.4.2 Whole-exome and whole-genome sequencing ............................................................ 31 1.4.3 Imputation .................................................................................................................... 32 1.4.4 Population genetic evidence ........................................................................................ 33 1.5 Asthma and allergy related traits .................................................................................... 34 1.5.1 Asthma and allergy pathophysiology ........................................................................... 35 1.5.2 Genetics of asthma, allergy and other related diseases ................................................ 36 1.5.3 Rare variants in asthma and allergies. .......................................................................... 39 1.5.4 Linking genetics to cellular trait to understand asthma and allergy related traits ....... 41 1.6 Leveraging founder and isolated populations to study complex traits ........................ 42 1.7 Rationale, objectives and hypothesis ............................................................................... 46 Chapter 2 ............................................................................................................... 48 Preface: Bridging Text between Chapters 1 and 2 .............................................................. 48 2.1 Abstract .............................................................................................................................. 50 2.2 Background ....................................................................................................................... 51 2.3 Methods .............................................................................................................................. 53 2 2.4 Results ................................................................................................................................ 61 2.5 Discussion .......................................................................................................................... 67 2.6 Conclusion ......................................................................................................................... 69 2.7 Acknowledgements ........................................................................................................... 70 2.8 Figures and Tables ............................................................................................................ 72 2.9 Supporting information .................................................................................................... 78 Chapter 3 ............................................................................................................. 100 Preface: Bridging Text between Chapters 2 and 3 ............................................................ 100 3.1 Abstract ............................................................................................................................ 102 3.2 Introduction ..................................................................................................................... 103 3.3 Material and Methods .................................................................................................... 105 3.4 Results .............................................................................................................................. 110 3.5 Discussion ........................................................................................................................ 114 3.7 Acknowledgements ......................................................................................................... 117 3.8 Figures and Tables .......................................................................................................... 118 3.9 Supplementary information ........................................................................................... 122 Chapter 4 ............................................................................................................. 139 Preface: Bridging Text between Chapters 3 and 4 ............................................................ 139 4.1 Abstract ............................................................................................................................ 141 4.2 Introduction ..................................................................................................................... 142 4.3 Materials and Methods ................................................................................................... 143 4.4 Results and Discussion .................................................................................................... 147 4.5 Acknowledgements ......................................................................................................... 150 4.6 Figure and Tables ........................................................................................................... 151 Chapter 5: Discussion and future directions .................................................... 154 References ............................................................................................................ 166 Appendix .............................................................................................................. 182 Significant Contribution by the author to other projects ................................................. 182 3 Abstract/Résumé Abstract In the past few years, genome-wide association studies (GWAS) allowed to identify a large number of common variants associated with multiple complex traits. These studies were a great tool that really helped understanding the genetic basis of a large number of diseases allowing to identify new pathways, better understand disease mechanisms and even pinpoint potential drug targets. However, most of the SNP identified were located in the non-coding region of the genome (~90%) and mainly had small effect size. Additionally, even the largest meta-analysis combining thousands of samples could not explain most of the diseases heritability. This forced the research community to develop new strategies and tools to complement GWAS findings. In this thesis, we explored some of these strategies to study asthma and allergy-related traits. These
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