Genetic Analysis of Complex Disease
Genetic Analysis of Complex Disease
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Author(s): Scott, Bill
ISBN No.: 9781118123911
Pages: 336
Year: 202112
Format: Trade Paper
Price: $ 202.79
Dispatch delay: Dispatched between 7 to 15 days
Status: Available

List of Contributors xv Foreword xvii 1 Designing a Study for Identifying Genes in Complex Traits 1 William K. Scott, Marylyn D. Ritchie, Jonathan L. Haines,and Margaret A. Pericak-Vance Introduction 1 Components of a Disease Gene Discovery Study 3 Define Disease Phenotype 4 Clinical Definition 4 Determining that a Trait Has a Genetic Component 5 Identification of Datasets 5 Develop Study Design 5 Family-Based Studies 6 Population-Based Studies 6 Approaches for Gene Discovery 7 Analysis 7 Genomic Analysis 7 Statistical Analysis 8 Bioinformatics 8 Follow-up 8 Variant Detection 8 Replication 9 Functional Studies 9 Keys to a Successful Study 10 Foster Interaction of Necessary Expertise 10 Develop Careful Study Design 11 References 11 2 Basic Concepts in Genetics 13 Kayla Fourzali, Abigail Deppen, and Elizabeth Heise Introduction 13 Historical Contributions 13 Segregation and Linkage Analysis 13 Hardy-Weinberg Equilibrium 14 DNA, Genes, and Chromosomes 17 Structure of DNA 17 Genes and Alleles 19 Genes and Chromosomes 20 Genes, Mitosis, and Meiosis 22 When Genes and Chromosomes Segregate Abnormally 25 Inheritance Patterns in Mendelian Disease 25 Autosomal Recessive 25 Autosomal Dominant 25 X-linked Inheritance 28 Mitochondrial Inheritance 29 Y-linked 29 Genetic Changes Associated with Disease/ Trait Phenotypes 29 Mutations Versus Polymorphisms 29 Point Mutations 30 Sickle Cell Anemia 30 Achondroplasia 30 Deletion/Insertion Mutations 31 Duchenne and Becker Muscular Dystrophy 31 Cystic Fibrosis 31 Charcot-Marie- Tooth Disease 31 Nucleotide Repeat Disorders 32 Susceptibility Versus Causative Genes 32 Summary 34 References 34 3 Determining the Genetic Component of a Disease 36 Allison Ashley Koch and Evadnie Rampersaud Introduction 36 Study Design 37 Selecting a Study Population 37 Population-Based 38 Clinic-Based 38 Ascertainment 38 Single Affected Individual 39 Relative Pairs 40 Extended Families 40 Healthy or Unaffected Controls 41 Ascertainment Bias 42 Approaches to Determining the Genetic Component of a Disease 44 Co-segregation with Chromosomal Abnormalities and Other Genetic Disorders 44 Familial Aggregation 44 Family History Approach 44 Example of Calculating Attributable Fraction 46 Correlation Coefficients 46 Twin and Adoption Studies 47 Recurrence Risk in Relatives of Affected Individuals 48 Heritability 49 Example Using Correlation Coefficients to Calculate Heritability 50 Segregation Analysis 51 Summary 52 References 53 4 Study Design for Genetic Studies 58 Dana C. Crawford and Logan Dumitrescu Introduction 58 Selecting a Study Population 58 Family- Based Studies (Linkage) 59 Family- Based Studies (Association) 60 Studies of Unrelated Individuals (Association) 61 Cohort Studies 61 Cross- Sectional Studies 66 Case- Control Studies 66 Other Study Designs 68 Biobanks 69 Other Biobanks 71 Biospecimens for Biobanks 72 Summary 73 References 74 5 Responsible Conduct of Research in Genetic Studies 79 Susan Estabrooks Hahn, Adam Buchanan, Chantelle Wolpert, and Susan H. Blanton Introduction 79 Research Regulations and Genetics Research 80 Addressing Pertinent ELSI in Genetic Research 83 Genetic Discrimination 83 Privacy and Confidentiality 84 Certificate of Confidentiality 85 Coding Data and Samples 85 Secondary Subjects 86 Future Use of Samples/Data Sharing 87 Handling of Research Results 88 CLIA Regulations: Separation of Research and Clinical Laboratories 89 Releasing Children''s Genetic Research Results 90 DNA Ownership 90 DNA Banking 90 Family Coercion 91 Practical Methods for Efficient High-Quality Genetic Research Services 91 The Investigator as the Genetic Study Coordinator 92 Time Spent 92 Recruitment 93 Support Groups and Organizations 93 Referrals from Health Care Providers 93 Research Databases and the Internet 94 Institution Databases 94 Medical Clinics 94 Recruitment by Family Members 95 Informed Consent 95 Vulnerable Populations 96 Minors 97 Persons with Cognitive Impairment 97 Data and Sample Collection 97 Sample Collection 97 Confirmation of Diagnosis 98 The Art of Field Studies 99 Referring for Additional Medical Services 99 Maintaining Contact with Participants 100 Future Considerations 100 References 100 6 Linkage Analysis 105 Susan H. Blanton Disease Gene Discovery 107 Ability to Detect Linkage 116 Real World Example of LOD Score Calculation and Interpretation 117 Disease Gene Localization 120 Multipoint Analysis 121 Effects of Misspecified Model Parameters in LOD Score Analysis 124 Impact of Incorrect Disease Allele Frequency 124 Impact of Incorrect Mode of Inheritance 125 Impact of Incorrect Disease Penetrance 125 Impact of Incorrect Marker Allele Frequency 126 Control of Scoring Errors 127 Genetic Heterogeneity 128 Practical Approach for Model-Based Linkage Analysis of Complex Traits 131 Nonparametric Linkage Analysis 133 Identity by State and Identity by Descent 134 Methods for Nonparametric Linkage Analysis 136 Tests for Linkage Using Affected Sibling Pairs (ASP) 137 Test Based on Identity by State 137 Tests Based on Identity by Descent in ASPs 138 Simple Tests 138 Tests Applicable When IBD Status Cannot Be Determined 139 Multipoint Affected Sib-Pair Methods 141 Handling Sibships with More Than 2 Affected Siblings 142 Methods Incorporating Affected Relative Pairs 142 NPL Analysis 143 Fitting Population Parameters 145 Power Analysis and Experimental Design Considerations for Qualitative Traits 147 Factors Influencing Power of Sib-pair Methods 147 The Example of Testicular Cancer 148 Examples of Sib-Pair Methods for Mapping Complex Traits 150 Mapping Quantitative Traits 151 Measuring Genetic Effects in Quantitative Traits 152 Study Design for Quantitative Trait Linkage Analysis 154 Haseman-Elston Regression 155 Variance Components Linkage Analysis 156 Nonparametric Methods 158 The Future 159 Software Available 160 References 160 7 Data Management 169 Stephen D.


Turner and William S. Bush Developing a Data Organization Strategy 170 A Brief Overview of Data Normalization 170 Database Management System (DBMS) and Structured Query Language (SQL) 172 Partitioning Data by Type 173 Sequence-Level Data 174 Sample-Level Data 174 Database Implementation 175 Hardware and Software Requirements 175 Implementation and Performance Tuning 175 Interacting with the Database Directly 176 Security 177 Other Tools for Data Management and Manipulation 177 R 177 PLINK 178 SAMtools 178 Workflow Management and Cloud Computing 178 Conclusion 179 References 179 8 Linkage Disequilibrium and Association Analysis 182 Eden R. Martin and Ren-HuaChung Introduction 182 Linkage Disequilibrium 182 Measures of Allelic Association 183 Causes of Allelic Association 184 Mapping Genes Using Linkage Disequilibrium 186 Tests of Association 187 Case-Control Tests 188 Test Statistics 188 Measures of Disease Association and Impact 189 Assessing Confounding Bias 191 Family-Based Tests of Association 192 The Transmission/Disequilibrium Test 192 Tests Using Unaffected Sibling Controls 194 Tests Using Extended Pedigrees 195 Regression and Likelihood-Based Methods 196 Association Tests with Quantitative Traits 197 Analysis of Haplotype Data 197 Genome-Wide Association Studies (GWAS) 198 Special Populations 199 HapMap 200 1000 Genomes Project 200 Summary 201 References 201 9 Genome-Wide Association Studies 205 Jacob L. McCauley, Yogasudha Veturi, Shefali Setia Verma, and Marylyn D. Ritchie Introduction 205 Definition of GWAS 206 Purpose of GWAS 206 Design 206 Technologies for High-Density Genotyping 206 Discrete and Quantitative Trait Analysis 208 Case-Control, Family-Based, and Cohort Study Designs 209 Statistical Power for Association and Correction for Testing Multiple Hypotheses 211 Data Analysis 212 Quality Control on Genotyping Call Data 212 Initial Genotyping Quality Control 213 Sample-Level Quality Control 214 SNP-Level Quality Control 215 Software Programs for Quality Control 215 Population Structure 216 Imputation 219 Genetic Association Testing 220 Meta-Analysis and "Mega-Analysis" 221 Whole-Genome Regression-Based GWAS 222 Conclusion 222 References 222

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