A Statistical Approach to Genetic Epidemiology: Concepts and Applications, with an e-Learning Platform, 2nd Edition

Foreword to the First Edition vii

Foreword to the Second Edition viii

Preface xi

Acknowledgments xv

1 Molecular Genetics 1

1.1 Genetic information 2

1.1.1 Location of genetic information 2

1.1.2 Interpretation of genetic information 5

1.1.3 Translation of genetic information 5

1.2 Transmission of genetic information 7

1.3 Variations in genetic information 10

1.3.1 Individual differences in genetic information 10

1.3.2 Detection of variations 12

1.3.3 Probability for detection of variations 16

1.4 Problems 18

2 Formal Genetics 21

2.1 Mendel and his laws 22

2.2 Segregation patterns 23

2.2.1 Autosomal dominant inheritance 24

2.2.2 Autosomal recessive inheritance 25

2.2.3 X-chromosomal dominant inheritance 26

2.2.4 X-chromosomal recessive inheritance 27

2.2.5 Y-chromosomal inheritance 28

2.3 Complications of Mendelian segregation 28

2.3.1 Variable penetrance and expression 29

2.3.2 Age-dependent penetrance 31

2.3.3 Imprinting 33

2.3.4 Phenotypic and genotypic heterogeneity 35

2.3.5 Complex diseases 36

2.4 Hardy–Weinberg law 38

2.5 Problems 43

3 Genetic Markers 47

3.1 Properties of genetic markers 47

3.2 Types of genetic markers 52

3.2.1 Short tandem repeats (STRs) 52

3.2.2 Single nucleotide polymorphisms (SNPs) 54

3.3 Genotyping methods for SNPs 57

3.3.1 Restriction fragment length polymorphism analysis 58

3.3.2 Real-time polymerase chain reaction 58

3.3.3 Matrix assisted laser desorption/ionization time of flight genotyping 61

3.3.4 Chip-based genotyping 61

3.3.5 Choice of genotyping method 63

3.4 Problems 65

4 Data Quality 67

4.1 Pedigree errors 68

4.2 Genotyping errors in pedigrees 70

4.2.1 Frequency of genotyping errors 70

4.2.2 Reasons for genotyping errors 71

4.2.3 Mendel checks 72

4.2.4 Checks for double recombinants 74

4.3 Genotyping errors and Hardy–Weinberg equilibrium (HWE) 76

4.3.1 Causes of deviations from HWE 77

4.3.2 Tests for deviation from HWE for SNPs 78

4.3.3 Tests for deviation from HWE for STRs 81

4.3.4 Measures for deviation from HWE 83

4.3.5 Tests for compatibility with HWE for SNPs 86

4.4 Quality control in high-throughput studies 91

4.4.1 Sample quality control 94

4.4.2 SNP quality control 97

4.5 Cluster plot checks and internal validity 98

4.5.1 Cluster compactness measures 101

4.5.2 Cluster connectedness measures 101

4.5.3 Cluster separation measures 101

4.5.4 Genotype stability measures 102

4.5.5 Combinations of criteria 102

4.6 Problems 109

5 Genetic Map Distances 113

5.1 Physical distance 113

5.2 Map distance 114

5.2.1 Distance 114

5.2.2 Specific map functions 115

5.2.3 Correspondence between physical distance and map distance 116

5.2.4 Multilocus feasibility 117

5.3 Linkage disequilibrium distance 118

5.4 Problems 123

6 Family Studies 125

6.1 Family history method and family study method 127

6.2 Familial correlations and recurrence risks 129

6.2.1 Familial resemblance 129

6.2.2 Recurrence risk ratios 131

6.3 Heritability 134

6.3.1 The simple Falconer model 135

6.3.2 The general Falconer model 137

6.3.3 Kinship coefficient and Jacquard’s Δ7 coefficient 138

6.4 Twin and adoption studies 141

6.4.1 Twin studies 141

6.4.2 Adoption studies 142

6.5 Critique on investigating familial resemblance 143

6.6 Segregation analysis 144

6.7 Problems 154

7 Model-Based Linkage Analysis 155

7.1 Linkage analysis between two genetic markers 156

7.1.1 Linkage analysis in phase-known pedigrees 156

7.1.2 Linkage analysis in phase-unknown pedigrees 160

7.1.3 Linkage analysis in pedigrees with missing genotypes 161

7.2 Linkage analysis between a genetic marker and a disease 167

7.2.1 Linkage analysis between a genetic marker and a disease in phase-known pedigrees 168

7.2.2 Linkage analysis between a genetic marker and a disease in general cases 172

7.2.3 Gain in information by genotyping additional individuals; power calculations 177

7.3 Significance levels in linkage analysis 180

7.4 Problems 184

8 Model-Free Linkage Analysis 189

8.1 The principle of similarity 190

8.2 Mathematical foundation of affected sib-pair analysis 192

8.3 Common tests for affected sib-pair analysis 193

8.3.1 The maximum LOD score and the triangle test 194

8.3.2 Score- and Wald–type 1 degree of freedom tests 201

8.3.3 Affected sib-pair tests using alleles shared identical by state 206

8.4 Properties of affected sib-pair tests 206

8.5 Sample size and power calculations for affected sib-pair studies 207

8.5.1 Functional relation between identical by descent probabilities and recurrence risk ratios 207

8.5.2 Sample size and power calculations for the mean test using recurrence risk ratios 209

8.6 Extensions to multiple marker loci 212

8.7 Extension to large sibships 213

8.8 Extension to large pedigrees 214

8.9 Extensions of the affected sib-pair approach 216

8.9.1 Covariates in affected sib-pair analyses 216

8.9.2 Multiple disease loci in affected sib-pair analyses 216

8.9.3 Estimating the position of the disease locus in affected sib-pair analyses 217

8.9.4 Typing unaffected relatives in sib-pair analyses 217

8.10 Problems 218

9 Quantitative Traits 221

9.1 Quantitative versus qualitative traits 222

9.2 The Haseman–Elston method 223

9.2.1 The expected squared phenotypic difference at the trait locus 225

9.2.2 The expected squared phenotypic difference at the marker locus 227

9.3 Extensions of the Haseman–Elston method 229

9.3.1 Double squared trait difference 230

9.3.2 Extension to large sibships 230

9.3.3 Haseman–Elston revisited and the new Haseman–Elston method 231

9.3.4 Power and sample size calculations 234

9.4 Variance components models 237

9.4.1 The univariate variance components model 237

9.4.2 The multivariate variance components model 238

9.5 Random sib-pairs, extreme probands and extreme sib-pairs 240

9.6 Empirical determination of p-values 243

9.7 Problems 245

10 Fundamental Concepts of Association Analyses 247

10.1 Introduction to association 247

10.1.1 Principles of association 247

10.1.2 Study designs for association 249

10.2 Linkage disequilibrium 250

10.2.1 Allelic linkage disequilibrium 250

10.2.2 Genotypic linkage disequilibrium 255

10.2.3 Extent of linkage disequilibrium 259

10.3 Problems 262

11 Association Analysis in Unrelated Individuals 265

11.1 Selection of cases and controls 266

11.2 Tests, estimates, and a comparison 266

11.2.1 Association tests 267

11.2.2 Choice of a test in applications 272

11.2.3 Effect measures 274

11.2.4 Selection of the genetic model 280

11.2.5 Association tests for the X chromosome 287

11.3 Sample size calculation 289

11.4 Population stratification 291

11.4.1 Testing for population stratification 293

11.4.2 Structured association 294

11.4.3 Genomic control 295

11.4.4 Comparison of structured association and genomic control 297

11.4.5 Principal components analysis 297

11.5 Gene-gene and gene-environment interaction 299

11.5.1 Classical examples for gene-gene and gene-environment interaction 299

11.5.2 Coat color in the Labrador retriever 301

11.5.3 Concepts of interaction 303

11.5.4 Statistical testing of gene-environment interactions 307

11.5.5 Statistical testing of gene-gene interactions 311

11.5.6 Multifactor dimensionality reduction 315

11.6 Problems 316

12 Family-based Association Analysis 319

12.1 Haplotype relative risk 320

12.2 Transmission disequilibrium test (TDT) 322

12.3 Risk estimates for trio data 325

12.4 Sample size and power calculations for the TDT 327

12.5 Alternative test statistics 329

12.6 TDT for multiallelic markers 330

12.6.1 Test of single alleles 330

12.6.2 Global test statistics 331

12.7 TDT type tests for different family structures 333

12.7.1 TDT type tests for missing parental data 334

12.7.2 TDT type tests for sibship data 336

12.7.3 TDT type tests for extended pedigrees 341

12.8 Association analysis for quantitative traits 344

12.9 Problems 346

13 Haplotypes in Association Analyses 349

13.1 Reasons for studying haplotypes 350

13.2 Inference of haplotypes 351

13.2.1 Algorithms for haplotype assignment 352

13.2.2 Algorithms for estimating haplotype probabilities 353

13.3 Association tests using haplotypes 356

13.4 Haplotype blocks and tagging SNPs 359

13.4.1 Selection of markers by haplotypes or linkage disequilibrium 360

13.4.2 Evaluation of marker selection approaches 363

13.5 Problems 364

14 Genome-wide Association (GWA) Studies 367

14.1 Design options in GWA studies 369

14.2 Genotype imputation 370

14.2.1 Imputation algorithms 370

14.2.2 Quality of imputation 371

14.3 Statistical analysis of GWA studies 372

14.4 Multiple testing 374

14.4.1 Region-wide multiple testing adjustment by simulation 375

14.4.2 Genome-wide multiple testing adjustment by simulation 376

14.4.3 Multiple testing adjustment by effective number of tests 377

14.5 Analysis of accumulating GWA data 378

14.5.1 Multistage designs for GWA studies 378

14.5.2 Replication in GWA studies 379

14.5.3 Meta-analysis of GWA studies 380

14.6 Clinical impact of a GWA study 383

14.6.1 Evaluation of a genetic predictive test 383

14.6.2 Clinical validity of a single genetic marker 385

14.6.3 Clinical validity of multiple genetic markers 386

14.7 Outlook 389

14.8 Problems 391

Appendix

Algorithms Used in Linkage Analyses 393

A.1 The Elston–Stewart algorithm 394

A.1.1 The fundamental ideas of the Elston–Stewart algorithm 394

A.1.2 The Elston–Stewart algorithm for a trait and a linked marker locus 400

A.2 The Lander–Green algorithm 401

A.2.1 The inheritance vector at a single genetic marker 401

A.2.2 The inheritance distribution given all genetic markers 405

A.3 The Cardon–Fulker algorithm 412

A.4 Problem 414

Solutions 415

References 451

Index 489