Genetic Analysis of Complex Disease

Genetic Analysis of Complex Disease

Haines, Jonathan L.; Pericak-Vance, Margaret A.

John Wiley & Sons Inc







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Foreword. Preface. Contributors. 1. Basic Concepts in Genetics and Linkage Analysis (Elizabeth C. Melvin and Marcy C. Speer). Introduction. Historical Contributions. Segregation and Linkage Analysis. Hardy-Weinberg Equilibrium. DNA, Genes, and Chromosomes. Structure of DNA. Genes and Alleles. Genes and Chromosomes. Inheritance Patterns in Mendelian Disease. Genetic Changes Associated with Disease/Trait Phenotypes. Point Mutations. Deletion/Insertion Mutations/ Novel Mechanisms of Mutation: Unstable DNA and Trinucleotide Repeats. Susceptibility Versus Causative Genes. Genes, Mitosis, and Meiosis. When Genes and Chromosomes Segregate Abnormally. Ordering and Spacing of Loci by Mapping Techniques. Physical Mapping. Genetic Mapping. Interference and Genetic Mapping. Meiotic Breakpoint Mapping. Disease Gene Discovery. Information Content in a Pedigree. Disease Gene Localization. Extensions to Complex Disease. Summary. References. 2. Defining Disease Phenotypes (Arthur S. Aylsworth). Introduction. Exceptions to Traditional Mendelian Inheritance Patterns. Pseudodominant Transmission of a Recessive. Pseudorecessive Transmission of a Dominant. Mosaicism. Mitochondrial Inheritance. Incomplete Penetrance and Variable Expressivity. Genomic Imprinting. Phenocopies and Other Environmentally Related Effects. Heterogeneity. Genetic Heterogeneity. Phenotypic Heterogeneity. Complex Inheritance. Polygenic and Multifactorial Models. Role of Environment. Role of Chance in Phenotype Expression. Phenotype Definition. Classification of Disease. Nonsyndromic Phenotypes. Syndromic Phenotypes. Associations and Syndromes of Unknown Cause. Importance of Chromosomal Rearrangements in Mapping. Qualitative (Discontinuous) and Quantitative (Continuous) Traits. Defining Phenotypes for Analysis of Complex Genetic Disorders. Select Most Biologically Meaningful Phenotype. Partition Phenotype or Dataset by Cause and Associated Pathology. Summary: Approach to Phenotype Definition. Resources for Information about Clinical Genetics and Phenotype Definition. References. 3. Determining Genetic Component of a Disease (Allison Ashley-Koch). Introduction . Study Design . Selecting a Study Population . Ascertainment. Approaches to Determining the Genetic Component of a Disease. Cosegregation with Chromosomal Abnormalities and Other Genetic Disorders. Familial Aggregation. Twin and Adoption Studies. Recurrence Risk in Relatives of Affected Individuals. Heritability. Segregation Analysis. Summary. References. 4. Patient and Family Participation in Genetic Research Studies Chantelle Wolpert, Amy Baryk Crunk, and Susan Estabrooks Hahn). Introduction. Step 1: Preparing to Initiate a Family Study. Confidentiality. Certificate of Confidentiality. Need for a Family Studies Director. Working with Human Subjects. Step 2: Ascertainment of Families for Studies. Family Recruitment. Informed Consent and Family Participaion. Step 3: Data Collection. Confirmation of Diagnosis. Art of Field Studies Special Issues in Family Studies. Step 4: Family Follow-Up. Need for Additional Medical Services. Duty to Recontact Research Participants. Maintaining Contact with Participants. Guidelines for Releasing Genetic Information. Genetic Testing of Children. Genetic Discrimination. DNA Banking. Future Considerations. Appendix. References 5. Collection of Biological Samples for DNA Analysis (effery M. Vance). Establishing Goals of Collection. Types of DNA Sample Collection. Venipuncture (Blood). Buccal Samples. Dried Blood. Tissue. DNA Extraction and Processing . Blood. Quantitation. Tissue Culture. Buccal Brushes. Dried Blood Cards. Fixed Tissue. Whole-Genome Amplification. Sample Management. Informed Consent/Security. References. 6. Methods of Genotyping (Jeffery M. Vance). Brief Historical Review of Markers Used for Genotyping. Restriction Fragment Length Polymorphisms. Variable Number of Tandem Repeat Markers. Short Tandem Repeats or Microsatellites. Single-Nucleotide Polymorphisms. Sources of Markers. Restriction Fragment Length Polymorphisms. Microsatellites. Single-Nucleotide Polymorphisms. PCR and Genotyping. Laboratory and Methodology Optimization, Optimization of Reagents. "I Can't Read a Marker, What Should I Do?" Marker Separation. Manual or Nonsequencer Genotyping. Loading Variants. DNA Pooling and Homozygosity Mapping/Detection Methode. Radioactive Methods (32P or 33P). Silver Stain. Fluorescence. SNP Detection. DNA Array or "Chip". Oligonucleotide Ligation Assay. Fluorescent Polarization. Taqman. Single-Base-Pair Extension. Pyrosequencing. Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Spectrometry. Invader and PCR-Invader Assays. Single-Strand Conformational Polymorphism. Denaturing High-Pressure Liquid Chromatography. Data Management. Objectivity. Genotype Integrity. Scoring. Standards. Quality Control. References. 7. Data Analysis Issues in Expression Profiling.(Simon Lin and Michael Hauser). Introduction. Serial Analysis of Gene Expression. Analysis of SAGE Libraries. Microarray Analysis. Data Preparation. Expression Data Matrix. Dimension Reduction of Features. Measures of Similarity between Objects. Unsupervised Machine Learning: Clustering. Supervised Machine Learning Data Visualization Other Types of Gene Expression Data Analysis. Biological Applications of Expression Profiling. References. 8. Information Management (Carol Haynes and Colette Blach). Information Planning. Needs Assessment. Information Flow. Plan Logical Database Model. Hardware and Software Requirements. Software Selection. System Administration. Database Administration. Database Implementation. Conversion. Performance Tuning. Data Integrity. User Interfaces. Security. Transmission Security. System Security. Patient Confidentiality. Pedigree Plotting and Data Manipulation Software. Summary. 9. Quantitative Trait Linkage Analysis (Jason H. Moore). Introduction to Quantitative Traits. Genetic Architecture. Study Design. Haseman-Elston Regression . Multipoint IBD Method. Variance Component Linkage Analysis. Nonparametric Methods. Future Directions. Summary. References. 10. Advanced Parametric Linkage Analysis (Silke Schmidt). Two-Point Analysis. Example of LOD Score Calculation and Interpretation. Effects of Misspecified Model Parameters in LOD Score Analysis. Impact of Misspecified Disease Allele Frequency. Impact of Misspecified Mode of Inheritance. Impact of Misspecified Disease Penetrances. Impact of Misspecified Marker Allele Frequency. Control of Scoring Errors. Genetic Heterogeneity. Multipoint Analysis. Practical Approaches for Model-Based Linkage Analysis of Complex Traits. Affecteds-Only Analysis. Maximized Maximum LOD Score. Heterogeneity LOD. MFLINK. Summary. References. 11. Nonparametric Linkage Analysis (Elizabeth R. Hauser, Jonathan Haines, and David E. Goldgar). Introduction. Background and Historical Framework. Identity by State and Identity by Descent. Measures of Familiality. Qualitative Traits. Measuring Genetic Effects in Quantitative Traits. Summary of Basic Concepts. Methods for Nonparametric Linkage Analysis. Tests for Linkage Using Affected Sibling Pairs (ASPs). Methods Incorporating Affected Relative Pairs. Power Analysis and Experimental Design Considerations for Qualitative Traits. Nonparametric Quantitative Trait Linkage Analysis. Power and Sampling Considerations for Mapping.Quantitative Trait Loci. Examples of Application of Sibpair Methods for Mapping Complex Traits. Additional Considerations in Nonparametric Linkage Analysis. 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 xii CONTENTS 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 CONTENTS xiii Mapping the Human Genome 424 Genetic Mapping 425 Radiation Hybrid Mapping 427 Physical Mapping 428 Public Data Repositories and Genome Browsers. Single-Nucleotide Polymorphisms. SNP Discovery. Utilizing SNPs. Computational SNP Resources. Model Organisms. Identifying Candidate Genes by Genomic Convergence. De Novo Annotation of Genes. Software Suites. Online Sequence Analysis Resources. Understanding Molecular Mechanisms of Disease. Assigning Gene Function. Looking Beyond Genome Sequence. Other Databases. Summary. References. 16. Designing a Study for Identifying. Genes in Complex Traits (Jonathan L. Haines and Margaret A. Pericak-Vance). Introduction. Components of a Disease Gene Discovery Study. Define Phenotype. Develop Study Design. Analysis. Follow-Up. Keys to a Successful Study. Foster Interaction of Necessary Expertise. Develop Careful Study Design. References. Index.
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