Statistical Genetics : Gene Mappin g through Linkag e and Associatio n

Transcription

1 Statistical Genetics : Gene Mappin g through Linkag e and Associatio n Benjamin M Neale Manuel AR Ferreira Sarah E Medlan d Danielle Posthuma

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3 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 DNA Recombination and Genetic Distance Genotyping Genotyping Technologies 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 Mendelian Inheritance Random Mating Polygenic Inheritance Kinship and Genetic Sharing Fisher's Model for a Single Locus Fisher's Model for Multiple Loci an d Environmental Effects Conclusion 4 1 Chapter 4 Introduction to statistics 4 3 Frühling V. Rijsdijk 4.1 Introduction Descriptive Statistics Inferential Statistics 48

4 Chapter 7 Principles of linkage analysis 11 3 Dale R. Nyholt 7.1 Gene Mapping Model-based Linkage Analysis Model-free Linkage Analysis o f Affection Traits Empirically Deriving Genome-wide Linkage Significance Conclusion 13 0 Chapter 8 Algorithms for IBD estimation 13 5 Goncalo R. Abecasi s 8.1 Introduction The Computational Problem : Dealing with Unknown Phase Analysis of Pedigree Data Practical Examples 14 3 Chapter 9 Regression methods for linkage analysis 15 3 Stacey S. Cherny 9.1 Introduction 153

5 9.2 Haseman-Elston Extensions to Haseman-Elston Full-pedigree Regression-based Linkage Simulation Studies Examples using MERLIN-regress Conclusion 17 5 Chapter 10 Variance components linkage analysis for quantitative traits 18 1 Danielle Posthuma and Hermine H. Mae s 10.1 Introduction The VC Linkage Model Conducting Variance Components Linkag e Analysis with MERLIN VC Linkage Analysis in General Structura l Equation Packages Conclusion 20 3 Chapter I I Extensions to univariate linkage analysis 20 7 Sarah E. Medland 11.1 Parent-of-Origin Effects Genotype-by-Environment Interaction X-chromosome Linkage 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 A Brief History of Multivariate Analysi s in Human Genetics/Twin Studies Trait Selection Multivariate VC Linkage Analysis Multivariate QTL Analyses : Practica l Issues 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 Sample Size Deviations in Trait Distribution Outliers Pedigree Errors Genotyping Errors 287

6 13.7 Marker Informativeness, Densit y and Genetic Map Quality Control Guidelines 30 0 ASSOCIATION ANALYSI S Chapter 14 Introduction to association 31 1 Danielle M. Dick 14.1 Introduction Methods Used in Association Concepts Central to Association The International HapMap Project Power to Detect Association Uses of Association Conclusion 31 9 Chapter IS Single-locus association models 32 3 Sophie van der Sluis and Danielle Posthum a 15.1 Introduction Association Analysis with Random Population Samples Case-control Studies Family-based Association Studies 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 GWAS GWAS SNP Genotyping an d Data Handling Preparing GWAS Data for Analysis Outline of GWAS Data Analysis Quality Control Copy Number Variation Descriptive Analyses of the ALS/Contro l GWAS Data Association Analyses of GWAS Data Additional Features in PLINK Future Developments Conclusion 39 1 Chapter 17 Haplotype estimation 39 5 Andrew P. Morris 17.1 Introduction Population-Based Haplotyp e Reconstruction 396

7 17.3 Family-Based Haplotyp e Reconstruction Using Estimated Haplotypes for Disease-Gene Mapping 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 Phased Versus Unphased Utility of Multimarker Tests WRAP Analysis Conclusion 44 6 Chapter 19 Linkage disequilibrium and tagging 45 1 Benjamin M. Neal e 19.1 Linkage Disequilibrium Statistics Block-like Nature of the Genome Tagging Population Differences Multiallelic Markers 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 Data Checks Linkage Disequilibrium Analysis Tagging Analysis Viewing PLINK Results in Haploview Additional Consideration s and Programs Conclusion 48 4 Chapter 21 Factors affecting power and type- 1 error in association 48 7 David M. Evans 21.1 Introduction Factors Affecting Power to Detec t Association Population Stratification Genotyping Error Genome-wide Association Calculating Power to Detect Association Conclusion 526

8 Chapter 22 Resampling approaches t o statistical inference 53 5 Michael C. Neale and Sarah E. Medland 22.1 Introduction Bootstrap Estimation 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