Genetic Analysis of Complex Diseases 2e

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.

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 StudiesSpecial 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.References5. 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 LearningData VisualizationOther 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 319Software Available for Nonparametric Linkage Analysis 322Summary 323References 32312. Linkage Disequilibrium and Association Analysis 329Eden R. MartinIntroduction 329Linkage Disequilibrium 330Measures of Allelic Association 330Causes of Allelic Association 331Mapping Genes Using Linkage Disequilibrium 334Tests for Association 335Case Control Tests 335Family Based Tests of Association 340Analysis of Haplotype Data 345Association Tests for Quantitative Traits 347Association and Genomic Screening 347Special Populations 348Summary 349References 34913. Sample Size and Power 355Yi Ju Li, Susan Shao, and Marcy SpeerIntroduction 355Power Studies for Linkage Analysis:Mendelian Disease 358Information Content of Pedigrees 358Computer Simulation Methods 359Definitions for Power Assessments 363xii CONTENTSPower Studies for Linkage Analysis: Complex Disease 365Discrete Traits 367Quantitative Traits 373Power Studies for Association Analysis 376Transmission/Disequilibrium Test for Discrete Traits 378Transmission/Disequilibrium Test for Quantitative Traits 380Case Control Study Design 380DNA Pooling 381Genomic Screening Strategies for Association Studies 381Simulation of Linkage and Association Program 382Summary 383Appendix 13.1: Example of Monte Carlo Simulation AssumingThat Trait and Marker Loci Are Unlinked to Each Other 384Appendix 13.2: Example LOD Score Results for Pedigreein Figure 13.2 385Appendix 13.3: Example of Simulation of Genetic MarkerGenotypes Conditional on Trait Phenotypes Allowing forComplete and Reduced Penetrance 386References 39314. Complex Genetic Interactions 397William K. Scott and Joellen M. SchildkrautIntroduction 397Evidence for Complex Genetic Interactions GeneticHeterogeneity 398Genetic Heterogeneity 398Gene Gene Interaction (Epistasis) 399Gene Environment Interaction 400Analytic Approaches to Detection of Complex Interactions 401Segregation Analysis 402Linkage Analysis 402Association Analysis 406Potential Biases 414Conclusion 415References 41515. Genomics and Bioinformatics 423Judith E. Stenger and Simon G. GregoryIntroduction 423Era of the Genome 423CONTENTS xiiiMapping the Human Genome 424Genetic Mapping 425Radiation Hybrid Mapping 427Physical Mapping 428Public 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.