Statistical Genetics : Gene Mappin g through Linkag e and Associatio n Benjamin M Neale Manuel AR Ferreira Sarah E Medlan d Danielle Posthuma
About the editors List of contributors Preface Acknowledgements Foreword by Nicholas G. Martin, Dorret I. Boomsma, Michael C. Neale, and Hermine H. Maes Abbreviations Statistical symbols xi xiii xvi i xi x xx i xx v xxvii THE BASICS Chapter I Introduction 1 Nicholas G. Marti n Chapter 2 Basics of DNA and genotyping 5 Jesen A. Fagerness and Dale R. Nyholt 2.1 DNA Structure 5 2.2 DNA Recombination and Genetic Distance 8 2.3 Genotyping 1 1 2.4 Genotyping Technologies 1 3 2.5 Conclusion 1 5 Chapter 3 Introduction to biometrical genetics 1 7 Johnny S.H. Kwan, Shaun Purcell and Pak C. Sham 3.1 Historical Background 1 7 3.2 Mendelian Inheritance 1 8 3.3 Random Mating 1 9 3.4 Polygenic Inheritance 2 1 3.5 Kinship and Genetic Sharing 2 3 3.6 Fisher's Model for a Single Locus 2 6 3.7 Fisher's Model for Multiple Loci an d Environmental Effects 36 3.8 Conclusion 4 1 Chapter 4 Introduction to statistics 4 3 Frühling V. Rijsdijk 4.1 Introduction 4 3 4.2 Descriptive Statistics 4 4 4.3 Inferential Statistics 48
Chapter 7 Principles of linkage analysis 11 3 Dale R. Nyholt 7.1 Gene Mapping 11 3 7.2 Model-based Linkage Analysis 114 7.3 Model-free Linkage Analysis o f Affection Traits 120 7.4 Empirically Deriving Genome-wide Linkage Significance 12 8 7.5 Conclusion 13 0 Chapter 8 Algorithms for IBD estimation 13 5 Goncalo R. Abecasi s 8.1 Introduction 13 5 8.2 The Computational Problem : Dealing with Unknown Phase 13 5 8.3 Analysis of Pedigree Data 13 7 8.4 Practical Examples 14 3 Chapter 9 Regression methods for linkage analysis 15 3 Stacey S. Cherny 9.1 Introduction 153
9.2 Haseman-Elston 15 3 9.3 Extensions to Haseman-Elston 15 4 9.4 Full-pedigree Regression-based Linkage 15 5 9.5 Simulation Studies 16 2 9.6 Examples using MERLIN-regress 17 3 9.7 Conclusion 17 5 Chapter 10 Variance components linkage analysis for quantitative traits 18 1 Danielle Posthuma and Hermine H. Mae s 10.1 Introduction 18 1 10.2 The VC Linkage Model 18 2 10.3 Conducting Variance Components Linkag e Analysis with MERLIN 18 7 10.4 VC Linkage Analysis in General Structura l Equation Packages 190 10.5 Conclusion 20 3 Chapter I I Extensions to univariate linkage analysis 20 7 Sarah E. Medland 11.1 Parent-of-Origin Effects 20 7 11.2 Genotype-by-Environment Interaction 21 6 11.3 X-chromosome Linkage 22 4 11.4 Implementation of Extensions to Univariate Linkage Analysis 23 1 Chapter 12 QTL detection in multivariat e data from sibling pairs 23 9 Jouke Jan Hottenga and Dorret L Boomsm a 12.1 Introduction 23 9 12.2 A Brief History of Multivariate Analysi s in Human Genetics/Twin Studies 24 0 12.3 Trait Selection 24 2 12.4 Multivariate VC Linkage Analysis 24 4 12.5 Multivariate QTL Analyses : Practica l Issues 25 1 12.6 Conclusion 25 8 Chapter 13 Factors affecting type-i erro r and power of linkage analysis 26 5 Manuel A.R. Ferreira 13.1 Selective Sampling 26 6 13.2 Sample Size 27 1 13.3. Deviations in Trait Distribution 278 13.4 Outliers 28 3 13.5 Pedigree Errors 28 5 13.6 Genotyping Errors 287
13.7 Marker Informativeness, Densit y and Genetic Map 290 13.8 Quality Control Guidelines 30 0 ASSOCIATION ANALYSI S Chapter 14 Introduction to association 31 1 Danielle M. Dick 14.1 Introduction 31 1 14.2 Methods Used in Association 31 1 14.3 Concepts Central to Association 31 4 14.4 The International HapMap Project 31 5 14.5 Power to Detect Association 31 7 14.6 Uses of Association 31 7 14.7 Conclusion 31 9 Chapter IS Single-locus association models 32 3 Sophie van der Sluis and Danielle Posthum a 15.1 Introduction 32 3 15.2 Association Analysis with Random Population Samples 32 5 15.3 Case-control Studies 32 9 15.4 Family-based Association Studies 33 3 15.5 Conclusion 35 1 Chapter 16 Analyzing genome-wide association study data: a tutorial using PLINK 35 5 Patrick F. Sullivan and Shaun Purcell 16.1 Introduction 35 5 16.2 GWAS 35 5 16.3 GWAS SNP Genotyping an d Data Handling 36 0 16.4 Preparing GWAS Data for Analysis 366 16.5 Outline of GWAS Data Analysis 370 16.6 Quality Control 37 0 16.7 Copy Number Variation 376 16.8 Descriptive Analyses of the ALS/Contro l GWAS Data 37 7 16.9 Association Analyses of GWAS Data 38 3 16.10 Additional Features in PLINK 390 16.11 Future Developments 39 1 16.12 Conclusion 39 1 Chapter 17 Haplotype estimation 39 5 Andrew P. Morris 17.1 Introduction 39 5 17.2 Population-Based Haplotyp e Reconstruction 396
17.3 Family-Based Haplotyp e Reconstruction 40 7 17.4 Using Estimated Haplotypes for Disease-Gene Mapping 41 1 17.5 Conclusion 41 8 Chapter 18 Regional multilocus association models 42 3 Jo Knight, Pak C. Sham, Shaun Purcell and Benjamin M. Neale 18.1 Introduction and Basic Methods 42 3 18.2 Phased Versus Unphased 42 6 18.3 Utility of Multimarker Tests 43 0 18.4 WRAP Analysis 43 4 18.5 Conclusion 44 6 Chapter 19 Linkage disequilibrium and tagging 45 1 Benjamin M. Neal e 19.1 Linkage Disequilibrium Statistics 45 1 19.2 Block-like Nature of the Genome 45 4 19.3 Tagging 45 7 19.4 Population Differences 45 9 19.5 Multiallelic Markers 46 0 19.6 Conclusion 46 1 Chapter 20 Practical guide to linkage disequilibriu m analysis and tagging using Haploview 46 7 David J. Bender and Julian B. Maller 20.1 Introduction 46 7 20.2 Data Checks 46 8 20.3 Linkage Disequilibrium Analysis 47 1 20.4 Tagging Analysis 47 3 20.5 Viewing PLINK Results in Haploview 47 6 20.6 Additional Consideration s and Programs 48 3 20.7 Conclusion 48 4 Chapter 21 Factors affecting power and type- 1 error in association 48 7 David M. Evans 21.1 Introduction 48 7 21.2 Factors Affecting Power to Detec t Association 48 8 21.3 Population Stratification 49 9 21.4 Genotyping Error 51 0 21.5 Genome-wide Association 51 5 21.6 Calculating Power to Detect Association 51 8 21.7 Conclusion 526
Chapter 22 Resampling approaches t o statistical inference 53 5 Michael C. Neale and Sarah E. Medland 22.1 Introduction 53 5 22.2 Bootstrap Estimation 53 7 22.3 Permutation Tests 54 4 Appendix I File formats 55 1 A1.1 Overview 55 1 A1.2 MERLIN/MERLIN-Regresss/Pedstats / Minx/QTDT/GRR 55 1 A1.3 WHAP 56 0 A1.4 Haploview 56 1 A1.5 PLINK 56 3 A1.6 Running programs in DOS versu s Unix/Linux 56 5 Online resources 56 9 Index 571