GENOME WIDE ASSOCIATION STUDIES OF CORONARY ARTERY DISEASE IN SINGAPOREAN CHINESE POPULATIONS KE TINGJING (Bachelor of Science, Zhe Jiang University, China) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHYLOSOPHY DEPARTMENT OF PAEDIATRICS NATIONAL UNIVERSITY OF SINGAPORE 2014 i DECLARATION I hereby declare that this thesis is my original work and it has been written by me in its entirety I have duly acknowledged all the sources of information which have been used in the thesis This thesis has also not been submitted for any degree in any university previously _ Ke Tingjing 20 August 2014 ii ACKNOWLEDGEMENTS I am very grateful to be funded by a research scholarship from the National University of Singapore, which provided me opportunities to study in Singapore I thank the generous funding of HUJ-CREATE Program of the National Research Foundation, Singapore (Project Number 370062002) to support our researches I would like to express my sincerest gratitude to my supervisor, Prof Heng Chew Kiat, for his guidance, patience and encourage along the way of my PhD Thank you for his great efforts in reviewing my manuscripts and thesis I greatly appreciate Prof.Yechiel Friedlander from Hebrew University and Rajkumar Dorajoo from Genome Institute of Singapore for their guidance and valuable comments in our weekly meetings My sincere thanks also go to Prof JianJun Liu, who accepted me as an attached student of GIS I benefited a lot from the resources in GIS and gained lots of technical supports from the statistician Low HuiQi in GIS I would like to thank her for her earnest teaching I also feel grateful to Adeline Foo, who spent her personal time helping me with my writing I want to acknowledge all the people I have ever worked with Thank you, Ms Lye Hui Jen, Ms Karen Lee, Ms Kee Bee Leng, Miss Goh Jun Mui, Miss HanYi, Miss Chang Xuling, Ms Low Chay Boon, Mr Bai Chen, Mr Sadiduddin Edbe Selamat, Ms Katherine Wang and Ms Catherine Cheng! iii TABLE OF CONTENTS TABLE OF CONTENTS iv SUMMARY viii LIST OF TABLES xi LIST OF FIGURES xii LIST OF ABBREVIATION xiv Chapter 1: Introduction 1.1 Overview of coronary artery disease 1.2 Overview of the epidemiology of coronary artery disease 1.3 Overview of the etiology of coronary artery disease 1.4 Research objectives and significances 12 Study I: Genome wide scan of single nucleotide polymorphisms associated with myocardial infarction –Chapter 12 Study II: Genome wide scan of single nucleotide polymorphisms associated with serum lipid concentrations–Chapter 12 Study III: Interactions between genetic variants of peroxisome proliferator activated receptor delta and epithelial membrane protein on high density lipoprotein cholesterol levels in the Singaporean Chinese—Chapter 13 Chapter Literature review 15 2.1 Pathology of coronary artery disease 15 2.1.1 Atherosclerosis 15 2.1.2 Biochemistry of plasma cholesterols 17 2.2 Approaches to studying genetic variants of coronary artery disease 21 2.3 Genome wide association studies of coronary artery disease and its risk factors lipids 23 2.3.1 GWAS of CAD 23 2.3.2 GWAS of lipids 27 2.4 Detecting interactions 31 2.5 Strategies of genome wide association studies 33 2.5.1 Genotype calling 33 2.5.2 Quality control 34 2.5.3 Population stratification 37 2.5.4 Imputation and frequentist test 39 2.5.5 Meta-analysis 41 2.5.6 Bonferroni correction 42 2.6 Mendelian randomization and implications of causality 42 iv 2.6.1 Mendelian randomization 43 2.6.2 Causality of HDL-C for MI 44 2.6.3 Causality of LDL-C for MI 45 2.6.4 Causality of TG for MI 46 Chapter 3: Study populations and methods 48 3.1 Study design and population 48 3.1.1 Singapore Chinese Health Study (Used in Studies I, II and III) 48 3.1.2 Singapore Prospective Study (Used in Studies II and III) 49 3.1.3 Singapore Eye Study (Used in Studies II and III) 51 3.1.4 Singapore Coronary Artery Genetics Study—Study I 52 3.2 Anthropometric measurements 53 3 Laboratory measurements 54 3.3.1 Singapore Chinese Health Study 54 3.3.2 Singapore Prospective Study 55 3.3.3 Singapore Eye Study 56 3.4 Genotyping 56 3.5 Quality control 57 3.5.1 Quality control of SCHS 58 3.5.2 Quality control of SCHS-SCADGENS combined dataset 58 3.5.3 Quality control of Singapore eye studies and SP2 59 3.6 Imputation 65 3.7 Methods for population stratification analysis 65 3.6.1 Genomic control 65 3.6.2 Principle Component Analysis 65 3.8 Methods for association analysis 73 3.9 URLs 73 Chapter 4: Genome wide scan of single nucleotide polymorphisms associated with coronary artery disease 75 4.1 Introduction 75 4.2 Methods 76 4.2.1 Study design and genotyping 76 4.2.2 Selection of index SNPs for MI 76 4.2.3 Statistical tests 76 4.3 Results 77 4.3.2 Association with MI 77 v 4.3.1 Index SNPs influencing MI 81 4.4 Discussion 83 4.5 Summary 85 Chapter 5: Genome wide scan of single nucleotide polymorphisms associated with serum lipid concentrations 86 5.1 Introduction 86 5.2 Methods 88 5.2.1 Study design and population 88 5.2.2 Laboratory measurements 88 5.2.3 Genotypes and quality control 89 5.2.5 Imputation 91 5.2.6 Linkage equilibrium 91 5.2.7 Examination of the relationships between SNPs associated with lipid concentrations and MI 91 5.2.8 Statistical tests 93 5.3 Results 93 5.3.1 Associations of SNP withHDL-C, LDL-C and TG 94 5.3.2 Conditional analysis of top genetic loci 100 5.3.3 Index SNPs influencing lipid levels 105 5.3.4 Association of index SNPs with MI 115 5.3.5 Examination of causal relationship between lipid and MI 117 5.4 Discussion 118 5.4.1 Association of SNPs with lipid traits 118 5.4.2 Index SNPs influencing lipids and MI 120 5.4.3 Causal relationship 123 5.5 Summary 123 Chapter 6: Interactions between genetic variants of peroxisome proliferator activated receptor delta and epithelial membrane protein on high density lipoprotein cholesterol levels in the Singaporean Chinese—Study III 125 6.1 Introduction 125 6.2 Methods 127 6.2.1 Study design and study populations 127 6.2.2 Candidate SNP selection 128 6.2.3 MicroRNA binding site prediction 129 6.2.4 LD pattern comparsion 129 6.2.5 Statistical analysis 129 vi 6.3 Results 131 6.3.1 Characteristics of populations 131 6.3.2 Associations of PPAR SNPs with HDL-C 133 6.3.3 Epistasis of PPARs variants on HDL-C 135 6.4 Discussion 141 6.5 Summary: 144 Chapter Conclusion 146 7.1 Main findings 146 7.2 Directions for future works 147 7.2.1 Increasing sample size to obatain a better power 147 7.2.2 Causality of lipid traits for MI 148 7.2.3 Identification of interactions 149 7.2.4 Identification of rare variants by next generation sequencing 151 Conclusion 152 BIBLIOGRAPHY 153 vii SUMMARY Coronary artery disease (CAD) is the major cause of morbidity and mortality worldwide Myocardial infarction (MI), namely heart attack, is a more severe phenotype of CAD The etiology of CAD is largely contributed by genetics and environmental exposures With an increasing number of studies on the impact of environmental exposures, several guidelines have been proposed and a reduced risk of CAD has been documented in individuals who adhere to the guidelines However, much less is known about the genetic basis of CAD Genome wide association analysis, which is a powerful tool to identify genetic variants, is commonly employed to identify novel genetic variants currently Most genome wide association studies (GWAS) have been conducted in Caucasians while few were carried out in Asia The overall aim of this dissertation was to elucidate the genetic basis in relation to CAD and its associated quantitative intermediate traits, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and triglycerides (TG) in Singaporean Chinese populations We first assembled 1,136 myocardial infarction (MI) cases and 1,243 controls from existing Singaporean Chinese cohorts to conduct GWAS, with the aim of discovering new susceptibility loci for CAD We did not observe any new genetic variants to be associated with MI but there were suggestive associations in several genes that are implicated in the biology of CAD such as vascular endothelial growth factor A We next conducted GWAS and metaanalyses on the intermediate quantitative traits of CAD, namely HDL-C, LDLviii C and TG in 2,003 Singaporean Chinese with stratification by their MI status In this study, 66 of the 174 genetic variants that were previously reported in Caucasians have been successfully replicated in the Singaporean Chinese, thus demonstrating the transferability of these genetic variants across ethnic groups Significant novel genome wide associations have also been discovered in 11 genetic variants for HDL-C, 18 for LDL-C and 22 for TG To determine the independent roles of these newly identified variants, conditional analysis was carried out to adjust the effect of index variants We found no evidence of genome wide significant associations for these variants after the conditioning A situation of missing heritability is encountered when individual genes cannot fully account for all the heritability of diseases that is expected to be contributed by genetic factors Like most if not all complex diseases, CAD is not spared from this phenomenon To address this issue, a gene-gene interaction study was carried out for peroxisome proliferator activated receptors (PPARs), which are the key upstream regulators in the HDL-C metabolic pathway A statistically significant interaction influencing HDL-C has been detected between PPARδ variant rs2267668 and epithelial membrane protein downstream variant rs7191411 (β=-0.19, P=1.19x10-10) after multiple-testing correction (corrected P significance threshold: 1.18x10-9) The interaction has been successfully replicated (meta-analysis β=-0.13, P=3.72x10-11) in two independent Chinese populations (N=1,872 and N=1,928) but not in the Malays and Indians ix These findings highlight the global transferability of the majority of genetic variants and the potential 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Singapore Coronary Artery Genetics Study xv SCES: Singapore Chinese Eye Study SCES: Singapore Chinese Eye Study SCHS: Singapore Chinese Health Study SiMES: Singapore Malay Eye Study SINDI: Singapore... that studies of coronary artery disease in Asia are conducted to address this increasing burden 1.3 Overview of the etiology of coronary artery disease The etiology of CAD is multifactorial, involving... findings 2.3.1 GWAS of CAD Genome wide association studies have identified multiple genetic variants associated with CAD Most of the associations have been replicated in independent studies, indicating