Genetic Analysis of Complex Disease

1 Cover

2 Title Page

3 Copyright Page

4 List of Contributors

5 Foreword

6 1 Designing a Study for Identifying Genes in Complex Traits Introduction Components of a Disease Gene Discovery Study Keys to a Successful Study References

7 2 Basic Concepts in Genetics Introduction Historical Contributions DNA, Genes, and Chromosomes Genes, Mitosis, and Meiosis Inheritance Patterns in Mendelian Disease Genetic Changes Associated with Disease/ Trait Phenotypes Susceptibility Versus Causative Genes Summary References

8 3 Determining the Genetic Component of a Disease Introduction Study Design Approaches to Determining the Genetic Component of a Disease Summary References

9 4 Study Design for Genetic Studies Introduction Selecting a Study Population Family‐Based Studies (Linkage) Family‐Based Studies (Association) Cohort Studies Cross‐Sectional Studies Case–Control Studies Other Study Designs Biobanks Other Biobanks Biospecimens for Biobanks Summary References

10 5 Responsible Conduct of Research in Genetic Studies Introduction Research Regulations and Genetics Research Addressing Pertinent ELSI in Genetic Research Practical Methods for Efficient High‐Quality Genetic Research Services References

11 6 Linkage Analysis Disease Gene Discovery Ability to Detect Linkage Real World Example of LOD Score Calculation and Interpretation Disease Gene Localization Multipoint Analysis Effects of Misspecified Model Parameters in LOD Score Analysis Impact of Incorrect Disease Allele Frequency Impact of Incorrect Mode of Inheritance Impact of Incorrect Disease Penetrance Impact of Incorrect Marker Allele Frequency Control of Scoring Errors Genetic Heterogeneity Practical Approach for Model‐Based Linkage Analysis of Complex Traits Nonparametric Linkage Analysis Identity by State and Identity by Descent Methods for Nonparametric Linkage Analysis Tests for Linkage Using Affected Sibling Pairs (ASP) Tests Based on Identity by Descent in ASPs Multipoint Affected Sib‐Pair Methods Methods Incorporating Affected Relative Pairs NPL Analysis Fitting Population Parameters Power Analysis and Experimental Design Considerations for Qualitative Traits Examples of Sib‐Pair Methods for Mapping Complex Traits Mapping Quantitative Traits Measuring Genetic Effects in Quantitative Traits Study Design for Quantitative Trait Linkage Analysis Variance Components Linkage Analysis Nonparametric Methods The Future References

12 7 Data Management Developing a Data Organization Strategy Database Management System (DBMS) and Structured Query Language (SQL) Database Implementation Other Tools for Data Management and Manipulation Conclusion References

13 8 Linkage Disequilibrium and Association Analysis Introduction Linkage Disequilibrium Summary References

14 9 Genome‐Wide Association Studies Introduction Design Data Analysis Conclusion References

15 10 Bioinformatics of Human Genetic Disease Studies Introduction Common Threads Genome Analysis Processing and Analysis of Genomic Data Bioinformatics Resources References

16 11 Complex Genetic Interactions/Data Mining/Dimensionality Reduction Human Diseases Are Complex Complexity of Biological Systems Statistical and Mathematical Concepts of Complex Genetic Models Analytic Approaches to the Detection of Complex Interactions Conclusion References

17 12 Sample Size, Power, and Data Simulation Introduction Sample Size and Power Power Calculations and Simulation Power Studies for Association Analysis Power Simulations for Linkage Analysis Summary References

18 Index

19 End User License Agreement

1 Chapter 2 Table 2.1 Useful applications of Hardy–Weinberg theory. Table 2.2 Differences between meiosis and mitosis. Table 2.3 Hallmarks of Mendelian inheritance patterns of different types. Table 2.4 Salient features of human repeat expansion diseases.

2 Chapter 3 Table 3.1 Association between sex of offspring and risk of expansion in fra... Table 3.2 The association between disease concordance rates in twins and di... Table 3.3 Adoptive studies and disease etiology. Table 3.4 Familial correlation and heritability estimates of pulmonary func...

3 Chapter 5Table 5.1 Resources regarding human subjects genetics research and regulati...Table 5.2 Information on the Genetic Information Nondiscrimination Act (GIN...

4 Chapter 6Table 6.1 Example development of genetic map using four linked Loci A, B, C ,...Table 6.2 LOD scores for pedigrees in Examples 1, 2, and 3.Table 6.3 Number of phase‐known, fully informative meioses needed to detect...Table 6.4 Two‐point linkage analysis for Alzheimer disease and D19S246.Table 6.5 Impact of misspecifying disease allele frequency on LOD score ana...Table 6.6 Impact of misspecifying mode of inheritance on LOD score analysis...Table 6.7 Impact of misspecifying disease penetrance on LOD score analysis.Table 6.8 Impact of misspecifying marker allele frequencies on LOD score an...Table 6.9 Expected percentage of affected pairs showing 0, 1, or 2 alleles ...Table 6.10 Analysis of IBS sharing probabilities for two siblings at a mark...Table 6.11 Results of simple Sibpair tests on IDDM data.Table 6.12 Expected LOD scores for mapping testicular cancer susceptibility...Table 6.13 Familial Correlations in Blood Pressure.

5 Chapter 7Table 7.1 Software and web resources.

6 Chapter 8Table 8.1 Measures of allelic association for alleles A and B at different l...Table 8.2 Case–control association studies: APOE‐4 allele and AD.Table 8.3 Summary of epidemiological measures.Table 8.4 2 × 2 Contingency table for case–control analysis.Table 8.5 Example of population stratification a.Table 8.6 Multiallelic TDT: T mhet a.Table 8.7 Transmission disequilibrium test and diabetes a.

7 Chapter 11Table 11.1 Penetrance values for combinations of genotypes from two SNPs ex...Table 11.2 Penetrance values for combinations of genotypes from two SNPs ex...

8 Chapter 12Table 12.1 The four possible outcomes of an experiment.Table 12.2 Practical considerations when determining sample size.Table 12.3 Number of sibships and nuclear families in variance component ...

1 Chapter 1 Figure 1.1 Steps in a Mendelian disease gene discovery (positional cloning) ... Figure 1.2 Study cycle for a complex trait gene identification study. Figure 1.3 Components of a complex disease study and expertise needed to con...

2 Chapter 2 Figure 2.1 Principles of Mendel’s first law of segregation of heritable char... Figure 2.2 Principles of Mendel’s second law of independent assortment with ... Figure 2.3 The DNA double helix is packaged and condensed in several differe... Figure 2.4 The genetic code and abbreviations for amino acids. Figure 2.5 Central dogma of genetics: DNA → RNA → protein. Figure 2.6 A G‐banded human male karyotype. Figure 2.7 The myotonic dystrophy (DM) and insulin receptor (INSR) genes are... Figure 2.8 Genetic results of crossing over: (a) no crossover: A and B remai... Figure 2.9 Genes that are on the same chromosome (syntenic) may be unlinked ... Figure 2.10 Pedigrees consistent with (a) autosomal dominant inheritance, (b... Figure 2.11 Single base pair changes in exon 4 of APOE define the 2, 3, and ...

3 Chapter 3 Figure 3.1 Ascertainment schemes for genetic analysis. Figure 3.2 Example of ascertainment bias in genetic analysis when ascertaini... Figure 3.3 Correlation of age of onset among siblings affected with Alzheime...

4 Chapter 6Figure 6.1 (a) Pedigree in which a rare, fully penetrant autosomal dominant ...Figure 6.2 (a) Pedigree in which a rare, fully penetrant autosomal dominant ...Figure 6.3 Pedigree for Example 3 for calculation of LOD score for linkageph...Figure 6.4 Pedigree examples demonstrating families that are informative and...Figure 6.5 Pedigree on the left shows unordered genotypes underneath pedigre...Figure 6.6 The most likely location for the disease gene is in the 7‐cM inte...Figure 6.7 Example of multipoint linkage analysis in the presence of genetic...Figure 6.8 Examples of identity by state and identity by descent. See text f...Figure 6.9 Example showing the inclusion of additional family members (here ...Figure 6.10 Power calculations for MLS sibpair analysis.