1 Springer. Nan M. Laird Christoph Lange. The Fundamentals of Modern Statistical Genetics

Transcription

1 1 Springer Nan M. Laird Christoph Lange The Fundamentals of Modern Statistical Genetics

2 1 Introduction to Statistical Genetics and Background in Molecular Genetics Basic Concepts in Genetic Disease Review of Molecular Genetics Types of Genetic Variants Effects of Genetic Variants on Disease Principles of Inheritance: Mendel's Laws and Genetic Models Mendel's Experiments A Framework for Genetic Models The Biology Underlying Mendelian Inheritance Exercises Some Basic Concepts from Population Genetics Estimation of Allele Frequencies Population Substructure Population Stratification Population Admixture Population Inbreeding Hardy-Weinberg Equilibrium Testing for HWE Some Causes of the Failure of HWE Measuring the Departure from HWE Exercises Aggregation, Heritability and Segregation Analysis: Modeling Genetic Inheritance Without Genetic Data Preliminaries Aggregation Analysis Estimating Recurrence Risk Ratios Further Simplifications o Heritability Analysis

3 0 xii Segregation Analysis Segregation Analysis for Dominant Mendelian Diseases Segregation Analysis for Recessive Mendelian Diseases Summary Exercises The General Concepts of Gene Mapping: Linkage, Association, Linkage Disequilibrium and Marker Maps Introduction Genetic Markers and Marker Maps Testing for Linkage or Association: Basic Concepts A Formal Definition of Linkage Disequilibrium and Related Measures Used to Describe Linkage Disequilibrium The Origin and Extent ofld in the Human Genome The Human Genome and HapMap Projects Exercises Basic Concepts of Linkage Analysis Basic Approach to Assessing Linkage Between Two Loci The Direct Counting Method The Interpretation of LOD Scores Exercises The Basics of Genetic Association Analysis Testing Association with Dichotomous Disease Traits: Codominant, Recessive and Dominant Models LO I 702 The Additive Genetic Model: The Alleles Test and the Trend Test Small Sample and Permutation Tests Which Mode of Inheritance Should We Assume for Testing? Estimating Effect Sizes and Confidence Intervals Examples of Testing Association with Diallelic Markers The Regression Approach: Extensions to Covariate Adjustment and to Other Phenotypes Association Analysis with Complex Traits: An Association Between INSIG2 and BMI Sample Size and Power Considerations for Case-Control Design Power and Effect Estimation: Testing a Marker in LD with the DSL o Exercises

4 s 11 Genome Wide Association Studies Introduction Quality-Control for the Genotype Data Multi-Stage Designs Testing Strategies for Family-Based Studies Replication, Non-replications and Meta-analysis Exercises xiii 8 Population Substructure in Association Studies The Impact of Population-Admixture and Stratification on Genetic Association Tests Genomic Control Approaches Modeling the Effects of Population Admixture and Stratification Regression-Based and Principal Component Approaches Exercises Association Analysis in Family Designs The Trio Design and the TDT Family Based Association Tests: FBAT Missing,Parents Comparative Power for Family-Based and Case-Control Designs Applications Using FBAT to Obtain the TDT Deriving a TDT for a Recessive Mode of Inheritance Informative Families Codominant Mode of Inheritance Multiallelic Test Using Unaffected Offspring Missing Parental Information Quantitative Traits Exercises Advanced Topics The Multiple Testing Problem in Association Studies Methods Based on P-Value Adjustment Permutation and Monte Carlo Tests Other Methods for the Analysis of Multiple SNPs, Including Haplotypes Gene-Environment/Gene-Drug Interaction Exercises

5 xiv 12 Looking Toward the Future A Basic Concepts of Linkage Analysis (Continued from Chapter 6) A.1 General Issues with Parametric Linkage Analysis A.2 Non-parametric Linkage Analysis A.3 Multipoint Linkage Analysis B A Class of Score Tests for Family Designs Properties of the Score Test Missing Parents C The TDT Tests for Both Linkage and Association (LD) Bibliography....' Index