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Integrating Population Genomics and Medical Genetics for Understanding the Genetic Aetiology of Eye Traits

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Integrating Population Genomics and Medical Genetics for Understanding the Genetic Aetiology of Eye Traits INTEGRATING POPULATION GENOMICS AND MEDICAL GENETICS FOR UNDERSTANDING THE GENETIC AETIOLOGY OF EYE TRAITS FAN QIAO (M.Sc. University of Minnesota) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSPHY SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH NATIONAL UNIVERSITY OF SINGAPORE 2012 Acknowledgements I would like to express my sincerest gratitude to my supervisor, Prof. Yik- Ying Teo, for his guidance, patience and encouraging high standards in my work through this study. He spent hours reviewing my original manuscripts, gave constructive feedback and made detailed corrections. His support has been invaluable for me to write this doctoral thesis. I am also deeply grateful to my supervisor, Prof. Seang-Mei Saw, for her continuous support, suggestions and providing research resources for me to accomplish my work. Her passion in research and the determination to slow the myopic progression in children has influenced me greatly. My sincere thanks also go to Dr. Yi-Ju Li, who encouraged me to move a step forward in my career and broadened my research experience. Her unflinching courage confronting ill health will inspire me for my whole life. I am also thankful to Dr. Ching-Yu Cheng. The conversations with Ching-Yu were always valuable for me to understand the clinical relevance of ocular diseases. My thanks are also due to Dr. Chiea-Chuen Khor for his prompt comments in reviewing my papers and the insight provided. I also wish to thank Dr. Liang Kee Goh for providing the infrastructure to support me at the beginning of this research, and Prof. Terri L Young and Prof. Tien-Yin Wong for their dedication along this project. During this research, I have worked with many collaborators for whom I have great regard. In particular, I am indebted to Dr. Veluchamy A. Barathi for performing gene and protein expression in ocular tissues. The discussion with her regarding the animal model of myopia was an interesting exploration. 1 It is also my pleasure to acknowledge Dr. Akira Meguro and Dr. Isao Nakata for kindly sharing their data in the replication study and stimulating discussions. Many thanks go to my office-mates and colleagues, Zhou Xin, Chen Peng, Xiaoyu, Haiyang, Huijun, Rick, Queenie, Vivian, Chenwei and Wang Pei for their cheerful discussion and a source of inspiration. Finally, I would like to thank my family for their wholehearted support given to me - I owe everything to them. For me, the journey over the past several years has been more like a process of cultivation. The best way to express my gratitude is, without attachment to a self, to help others in my life. 2 Tables of Contents SUMMARY…………………………………………………………………..6 LIST OF TABLES………………………………………………...................8 LIST OF FIGURES………………………………………………….............9 1 CHAPTER 1 INTRODUCTION ............................................................. 12 1.1 Statistical analysis of genome-wide association studies ....................................... 12 1.1.1 Linkage disequilibrium based association mapping................................................ 12 1.1.2 Study design and analytical strategy ....................................................................... 13 1.1.2.1 Data quality control ........................................................................................ 13 1.1.2.2 Population structure ....................................................................................... 14 1.1.2.3 Study design ................................................................................................... 16 1.1.2.4 Multiple testing .............................................................................................. 17 1.1.3 Phenotype classification.......................................................................................... 18 1.1.3.1 Binary/quantitative traits ................................................................................ 18 1.1.3.2 Paired eye measurements ............................................................................... 19 1.1.4 Meta-analysis of genome-wide association studies ................................................ 22 1.1.4.1 Imputation on genotyped data ........................................................................ 22 1.1.4.2 Statistics in the meta-analysis ........................................................................ 23 1.1.4.3 Statistical challenges in analyzing multi-ethnic populations .......................... 26 1.2 Recombination variation between populations .................................................... 28 1.2.1 Recombination and genetic diversity ...................................................................... 28 1.2.2 Variation in inter-population recombination ........................................................... 29 1.2.3 Current approaches of quantifying recombination differences ............................... 30 1.3 Refractive errors and the aetiology of myopia ..................................................... 32 1.3.1 Types of refractive errors ........................................................................................ 33 1.3.1.1 Myopia, hyperopia and ocular biometrics ...................................................... 33 1.3.1.2 Astigmatism ................................................................................................... 34 1.3.2 Experimental animal myopia models ...................................................................... 35 1.3.2.1 Deprivation myopia and inducing myopia ..................................................... 35 1.3.2.2 Emmetropisation and the role of scleral changes in eye growth .................... 37 1.3.2.3 Peripheral refraction ....................................................................................... 37 1.3.3 Roles of environmental factors in controlling human refraction ............................ 38 1.3.4 Genetic basis of myopia .......................................................................................... 41 1.3.4.1 Familial aggregation and segregation............................................................. 41 1.3.4.2 Estimates of heritability ................................................................................. 43 1.3.5 Genetic loci associated with or linked to refractive errors ...................................... 46 1.3.5.1 Myopic loci identified from genome-wide linkage studies ............................ 46 1.3.5.2 Candidate gene studies ................................................................................... 50 1.3.5.3 Genome-wide association studies .................................................................. 57 3 1.3.6 Intervention to slow myopia progression ................................................................ 61 2 CHAPTER 2 STUDY AIMS ....................................................................... 65 3 CHAPTER 3 GENETIC VARIANTS ON CHROMOSOME 1Q41 INFLUENCE OCULAR AXIAL LENGTH AND HIGH MYOPIA ........ 67 3.1 Abstract ................................................................................................................ 67 3.2 Background .......................................................................................................... 68 3.3 Methods ................................................................................................................ 70 3.3.1 Study cohorts .......................................................................................................... 70 3.3.2 Data quality control ................................................................................................ 74 3.3.3 Statistical methods .................................................................................................. 77 3.3.4 Functional studies ................................................................................................... 78 3.3.4.1 Gene expression in human ............................................................................. 78 3.3.4.2 Myopia-induced mouse model ....................................................................... 79 3.4 Results .................................................................................................................. 82 3.4.1 Datasets after quality control .................................................................................. 82 3.4.2 Locus at chromosome 1q41 achieved genome-wide significance .......................... 83 3.4.3 Association with high myopia on the identified SNPs ............................................ 84 3.4.4 Gene expression ...................................................................................................... 85 3.5 Discussion ............................................................................................................. 86 4 CHAPTER 4 GENOME-WIDE META-ANALYSIS OF FIVE ASIAN COHORTS IDENTIFIES PDGFRA AS A SUSCEPTIBILITY LOCUS FOR CORNEAL ASTIGMATISM ............................................... 103 4.1 Abstract .............................................................................................................. 103 4.2 Background ........................................................................................................ 104 4.3 Methods .............................................................................................................. 106 4.3.1 Study cohorts ........................................................................................................106 4.3.2 Data quality control ..............................................................................................109
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