Genetic Analysis of Complex Disease

Second Edition features the latest tools for uncovering the genetic basis of human disease The Second Edition of this landmark publication brings together a team of leading experts in the field to thoroughly update the publication. Readers will discover the tremendous advances made in human genetics in the seven years that have elapsed since the First Edition. Once again, the editors have assembled a comprehensive introduction to the strategies, designs, and methods of analysis for the discovery of genes in common and genetically complex traits. The growing social, legal, and ethical issues surrounding the field are thoroughly examined as well. Rather than focusing on technical details or particular methodologies, the editors take a broader approach that emphasizes concepts and experimental design. Readers familiar with the First Edition will find new and cutting-edge material incorporated into the text: Updated presentations of bioinformatics, multiple comparisons, sample size requirements, parametric linkage analysis, case-control and family-based approaches, and genomic screening New methods for analysis of gene-gene and gene-environment interactions A completely rewritten and updated chapter on determining genetic components of disease New chapters covering molecular genomic approaches such as microarray and SAGE analyses using single nucleotide polymorphism (SNP) and cDNA expression data, as well as quantitative trait loci (QTL) mapping The editors, two of the world's leading genetic epidemiologists, have ensured that each chapter adheres to a consistent and high standard. Each one includes all-new discussion questions and practical examples. Chapter summaries highlight key points, and a list of references for each chapter opens the door to further investigation of specific topics. Molecular biologists, human geneticists, genetic epidemiologists, and clinical and pharmaceutical researchers will find the Second Edition a helpful guide to understanding the genetic basis of human disease, with its new tools for detecting risk factors and discovering treatment strategies.

Table of Contents:
Foreword xv Preface xvii Contributors xix 1. Basic Concepts in Genetics and Linkage Analysis 1 Elizabeth C. Melvin and Marcy C. Speer Introduction 1 Historical Contributions 2 Segregation and Linkage Analysis 2 Hardy–Weinberg Equilibrium 5 DNA, Genes, and Chromosomes 5 Structure of DNA 5 Genes and Alleles 9 Genes and Chromosomes 10 Inheritance Patterns in Mendelian Disease 13 Genetic Changes Associated with Disease/Trait Phenotypes 14 Point Mutations 14 Deletion/Insertion Mutations 17 Novel Mechanisms of Mutation: Unstable DNA and Trinucleotide Repeats 18 Susceptibility Versus Causative Genes 19 Genes, Mitosis, and Meiosis 23 When Genes and Chromosomes Segregate Abnormally 25 Ordering and Spacing of Loci by Mapping Techniques 26 Physical Mapping 26 Genetic Mapping 29 Interference and Genetic Mapping 30 Meiotic Breakpoint Mapping 31 Disease Gene Discovery 31 Information Content in a Pedigree 41 Disease Gene Localization 42 Extensions to Complex Disease 45 Summary 45 References 46 2. Defining Disease Phenotypes 51 Arthur S. Aylsworth Introduction 51 Exceptions to Traditional Mendelian Inheritance Patterns 52 Pseudodominant Transmission of a Recessive 53 Pseudorecessive Transmission of a Dominant 54 Mosaicism 55 Mitochondrial Inheritance 56 Incomplete Penetrance and Variable Expressivity 58 Genomic Imprinting 61 Phenocopies and Other Environmentally Related Effects 63 Heterogeneity 64 Genetic Heterogeneity 64 Phenotypic Heterogeneity 65 Complex Inheritance 67 Polygenic and Multifactorial Models 67 Role of Environment 70 Role of Chance in Phenotype Expression 70 Phenotype Definition 71 Classification of Disease 71 Nonsyndromic Phenotypes 72 Syndromic Phenotypes 72 Associations and Syndromes of Unknown Cause 73 Importance of Chromosomal Rearrangements in Mapping 74 Qualitative (Discontinuous) and Quantitative (Continuous) Traits 74 Defining Phenotypes for Analysis of Complex Genetic Disorders 75 Select Most Biologically Meaningful Phenotype 75 Partition Phenotype or Dataset by Cause and Associated Pathology 75 Summary: Approach to Phenotype Definition 80 Resources for Information about Clinical Genetics and Phenotype Definition 82 References 82 3. Determining Genetic Component of a Disease 91 Allison Ashley-Koch Introduction 91 Study Design 92 Selecting a Study Population 93 Ascertainment 94 Approaches to Determining the Genetic Component of a Disease 99 Cosegregation with Chromosomal Abnormalities and Other Genetic Disorders 100 Familial Aggregation 101 Twin and Adoption Studies 104 Recurrence Risk in Relatives of Affected Individuals 105 Heritability 107 Segregation Analysis 108 Summary 110 References 111 4. Patient and Family Participation in Genetic Research Studies 117 Chantelle Wolpert, Amy Baryk Crunk, and Susan Estabrooks Hahn Introduction 117 Step 1: Preparing to Initiate a Family Study 118 Confidentiality 118 Certificate of Confidentiality 119 Need for a Family Studies Director 119 Working with Human Subjects 122 Step 2: Ascertainment of Families for Studies 124 Family Recruitment 124 Informed Consent and Family Participation 128 Step 3: Data Collection 131 Confirmation of Diagnosis 131 Art of Field Studies 132 Special Issues in Family Studies 133 Step 4: Family Follow-Up 135 Need for Additional Medical Services 135 Duty to Recontact Research Participants 136 Maintaining Contact with Participants 137 Guidelines for Releasing Genetic Information 137 Genetic Testing of Children 139 Genetic Discrimination 139 DNA Banking 141 Future Considerations 142 Appendix 142 References 148 5. Collection of Biological Samples for DNA Analysis 153 Jeffery M. Vance Establishing Goals of Collection 153 Types of DNA Sample Collection 153 Venipuncture (Blood) 153 Buccal Samples 155 Dried Blood 156 Tissue 156 DNA Extraction and Processing 157 Blood 157 Quantitation 157 Tissue Culture 159 Buccal Brushes 160 Dried Blood Cards 161 Fixed Tissue 161 Whole-Genome Amplification 161 Sample Management 162 Informed Consent/Security 164 References 164 6. Methods of Genotyping 167 Jeffery M. Vance Brief Historical Review of Markers Used for Genotyping 167 Restriction Fragment Length Polymorphisms 167 Variable Number of Tandem Repeat Markers 168 Short Tandem Repeats or Microsatellites 168 Single-Nucleotide Polymorphisms 168 Sources of Markers 168 Restriction Fragment Length Polymorphisms 169 Microsatellites 169 Single-Nucleotide Polymorphisms 171 PCR and Genotyping 171 Laboratory and Methodology Optimization 171 Optimization of Reagents 172 “I Can’t Read a Marker, What Should I Do?” 173 Marker Separation 175 Manual or Nonsequencer Genotyping 175 Loading Variants 176 DNA Pooling and Homozygosity Mapping 177 Detection Methods 178 Radioactive Methods (32P or 33P) 178 Silver Stain 178 Fluorescence 179 SNP Detection 181 DNA Array or “Chip” 181 Oligonucleotide Ligation Assay 181 Fluorescent Polarization 182 Taqman 182 Single-Base-Pair Extension 184 Pyrosequencing 184 Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Spectrometry 184 Invader and PCR-Invader Assays 184 Single-Strand Conformational Polymorphism 186 Denaturing High-Pressure Liquid Chromatography 186 Data Management 186 Objectivity 187 Genotype Integrity 187 Scoring 187 Standards 187 Quality Control 188 References 189 7. Data Analysis Issues in Expression Profiling 193 Simon Lin and Michael Hauser Introduction 193 Serial Analysis of Gene Expression 194 Analysis of SAGE Libraries 195 Microarray Analysis 196 Data Preparation 197 Expression Data Matrix 198 Dimension Reduction of Features 198 Measures of Similarity between Objects 200 Unsupervised Machine Learning: Clustering 201 Supervised Machine Learning 204 Data Visualization 207 Other Types of Gene Expression Data Analysis 207 Biological Applications of Expression Profiling 209 References 212 8. Information Management 219 Carol Haynes and Colette Blach Information Planning 220 Needs Assessment 220 Information Flow 222 Plan Logical Database Model 223 Hardware and Software Requirements 225 Software Selection 226 System Administration 226 Database Administration 226 Database Implementation 227 Conversion 227 Performance Tuning 228 Data Integrity 228 User Interfaces 231 Security 231 Transmission Security 231 System Security 233 Patient Confidentiality 233 Pedigree Plotting and Data Manipulation Software 234 Summary 235 9. Quantitative Trait Linkage Analysis 237 Jason H. Moore Introduction to Quantitative Traits 237 Genetic Architecture 238 Study Design 240 Haseman–Elston Regression 240 Multipoint IBD Method 242 Variance Component Linkage Analysis 243 Nonparametric Methods 246 Future Directions 247 Summary 249 References 250 10. Advanced Parametric Linkage Analysis 255 Silke Schmidt Two-Point Analysis 256 Example of LOD Score Calculation and Interpretation 259 Effects of Misspecified Model Parameters in LOD Score Analysis 260 Impact of Misspecified Disease Allele Frequency 261 Impact of Misspecified Mode of Inheritance 262 Impact of Misspecified Disease Penetrances 263 Impact of Misspecified Marker Allele Frequency 264 Control of Scoring Errors 265 Genetic Heterogeneity 266 Multipoint Analysis 269 Practical Approaches for Model-Based Linkage Analysis of Complex Traits 273 Affecteds-Only Analysis 274 Maximized Maximum LOD Score 275 Heterogeneity LOD 275 MFLINK 276 Summary 277 References 277 11. Nonparametric Linkage Analysis 283 Elizabeth R. Hauser, Jonathan Haines, and David E. Goldgar Introduction 283 Background and Historical Framework 284 Identity by State and Identity by Descent 286 Measures of Familiality 289 Qualitative Traits 289 Measuring Genetic Effects in Quantitative Traits 293 Summary of Basic Concepts 295 Methods for Nonparametric Linkage Analysis 295 Tests for Linkage Using Affected Sibling Pairs (ASPs) 295 Methods Incorporating Affected Relative Pairs 301 Power Analysis and Experimental Design Considerations for Qualitative Traits 311 Nonparametric Quantitative Trait Linkage Analysis 314 Power and Sampling Considerations for Mapping Quantitative Trait Loci 316 Examples of Application of Sibpair Methods for Mapping Complex Traits 318 Additional Considerations in Nonparametric Linkage Analysis 319 WPC Analysis 319 Software Available for Nonparametric Linkage Analysis 322 Summary 323 References 323 12. Linkage Disequilibrium and Association Analysis 329 Eden R. Martin Introduction 329 Linkage Disequilibrium 330 Measures of Allelic Association 330 Causes of Allelic Association 331 Mapping Genes Using Linkage Disequilibrium 334 Tests for Association 335 Case–Control Tests 335 Family-Based Tests of Association 340 Analysis of Haplotype Data 345 Association Tests for Quantitative Traits 347 Association and Genomic Screening 347 Special Populations 348 Summary 349 References 349 13. Sample Size and Power 355 Yi-Ju Li, Susan Shao, and Marcy Speer Introduction 355 Power Studies for Linkage Analysis: Mendelian Disease 358 Information Content of Pedigrees 358 Computer Simulation Methods 359 Definitions for Power Assessments 363 Power Studies for Linkage Analysis: Complex Disease 365 Discrete Traits 367 Quantitative Traits 373 Power Studies for Association Analysis 376 Transmission/Disequilibrium Test for Discrete Traits 378 Transmission/Disequilibrium Test for Quantitative Traits 380 Case–Control Study Design 380 DNA Pooling 381 Genomic Screening Strategies for Association Studies 381 Simulation of Linkage and Association Program 382 Summary 383 Appendix 13.1: Example of Monte Carlo Simulation Assuming That Trait and Marker Loci Are Unlinked to Each Other 384 Appendix 13.2: Example LOD Score Results for Pedigree in Figure 13.2 385 Appendix 13.3: Example of Simulation of Genetic Marker Genotypes Conditional on Trait Phenotypes Allowing for Complete and Reduced Penetrance 386 References 393 14. Complex Genetic Interactions 397 William K. Scott and Joellen M. Schildkraut Introduction 397 Evidence for Complex Genetic Interactions Genetic Heterogeneity 398 Genetic Heterogeneity 398 Gene–Gene Interaction (Epistasis) 399 Gene–Environment Interaction 400 Analytic Approaches to Detection of Complex Interactions 401 Segregation Analysis 402 Linkage Analysis 402 Association Analysis 406 Potential Biases 414 Conclusion 415 References 415 15. Genomics and Bioinformatics 423 Judith E. Stenger and Simon G. Gregory Introduction 423 Era of the Genome 423 Mapping the Human Genome 424 Genetic Mapping 425 Radiation Hybrid Mapping 427 Physical Mapping 428 Public Data Repositories and Genome Browsers 432 Single-Nucleotide Polymorphisms 434 SNP Discovery 435 Utilizing SNPs 436 Computational SNP Resources 437 Model Organisms 438 Identifying Candidate Genes by Genomic Convergence 439 De Novo Annotation of Genes 440 Software Suites 441 Online Sequence Analysis Resources 441 Understanding Molecular Mechanisms of Disease 442 Assigning Gene Function 442 Looking Beyond Genome Sequence 444 Other Databases 445 Summary 446 References 448 16. Designing a Study for Identifying. Genes in Complex Traits 455 Jonathan L. Haines and Margaret A. Pericak-Vance Introduction 455 Components of a Disease Gene Discovery Study 457 Define Phenotype 459 Develop Study Design 460 Analysis 463 Follow-Up 464 Keys to a Successful Study 465 Foster Interaction of Necessary Expertise 465 Develop Careful Study Design 466 References 467 Index 469

About the Author :
JONATHAN L. HAINES is Director of the Program in Human Genetics, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine. His research into the localization and identification of genes involved in human disease includes studying Alzheimer's disease, multiple sclerosis, Parkinson's disease, autism, macular degeneration, and other complex diseases. MARGARET A. PERICAK-VANCE is Director of the Center for Human Genetics and Chief of the Section of Medical Genetics in the Department of Medicine, Duke University School of Medicine. She is a founding Fellow of the American College of Medical Genetics. Her research interests include the integration of genomic and statistical technologies and their application to diseases of importance to public health, with an emphasis on neurologic diseases.