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From the Publisher"Genetic Dissection of Complex Traits provides an extensive overview of contemporary methods for statistical gene mapping."
—Alexandre A. Todorov for AMERICAN JOURNAL OF HUMAN GENETICS (July 2002)
Genetic Dissection of Complex Traits will present the full range of methodologies that are essential for understanding the basis of human genetic disorders, the origin of such diseases, and theories on how to determine one's genetic predisposition to certain genetic diseases.
Audience: Graduate students, scientists, and clinicians working in genetic research.
NEWTON MORTON'S CONTRIBUTIONS
Newton Morton: The Wisconsin Years.
Newton Morton's Influence on Genetics: The Morton Number.
OVERVIEW AND PRELIMINARIES
Genetic Dissection of Complex Traits: An Overview.
Familial Resemblance and Heritability.
Linkage and Association: Basic Concepts.
PHENOTYPES AND GENOTYPES
Definition of the Phenotype.
Genotyping for Human Whole-Genome Scans: Past, Present, and Future.
MODEL-BASED METHODS FOR LINKAGE ANALYSIS
The Lod Score Method.
Extension of the Lod Score: The Mod Score.
Major Strengths and Weaknesses of the Lod Score Method.
MODEL-FREE METHODS FOR LINKAGE AND ASSOCIATION ANALYSIS
Overview of Model-free Methods for Linkage Analysis.
Variance Component Methods for Detecting Complex Trait Loci.
Linkage and Association with Structural Relationships.
The Future of Genetic Case-Control Studies.
Cost of Linkage versus Association Methods.
Genotype-Environment Interaction in Transmission Disequilibrium Tests.
Major Strengths and Weaknesses of Model-free Methods.
MORE RECENT METHODS
Meta-analysis for Model-free Methods.
Classification Methods for Confronting Heterogeneity.
Applications of Neural Networks for Gene Finding.
Genome Partitioning and Whole-Genome Analysis.
Deciphering the Genetic Architecture of a Multivariate Phenotype.
On the Resolution and Feasibility of Genome Scanning Approaches.
One-Stage versus Two-Stage Strategies for Genome Scans.
MULTIPLE COMPARISONS AND SIGNIFICANCE LEVELS
Significance Levels in Genome Scans.
False Positives and False Negatives in Genome Scans.
Sequential Methods of Analysis for Genome Scans.
CHALLENGES FOR THE NEW MILLENNIUM
From Genetics to Mechanism of Disease Liability.
Complex Inheritance: The 21st Century.
Appendix: Research Contributions of Newton E. Morton.
This volume is based on a symposium held in honor of one of the founding fathers of genetic epidemiology, Newton E. Morton, on the occasion of his 70th birthday. We hope that it constitutes a fitting tribute to the man who continues to make pioneering contributions to the field.
The primary goal of this volume is to ask how best to even partially achieve the genetic dissection of complex traits, which do not have simple, single-gene causes. Toward that goal, this volume documents state-of-the-art methods and strategies and provides guidelines for undertaking the genetic dissection of complex traits. Is genetic dissection of complex traits achievable? The answer seems to be a resounding "yes," now more than ever before. This is an exciting time to be a genetic epidemiologist, with unprecedented new opportunities unfolding that we could only dream of a few short years ago. At the same time, we must recognize the limitations of some of the current approaches. It is generally recognized that genes and environments affect most human biological processes in complex and often interacting ways. Investigators the world over may be divided by differences in language and methodologies, but they are united in the conviction that genetic dissection of complex traits, though a formidable challenge, is possible.
Recent failures have actually strengthened our resolve to succeed. The recent years have witnessed a flurry of activity, in the development of novel methods as well as promising new strategies. Therefore, the time is ripe to undertake a realistic evaluation of contemporary methods, to critique their real utility, and to project promising new directions. Toward this end, the current volume, written by leading experts in genetic epidemiology, has three objectives. First, to provide a comprehensive and well-balanced review intended to quickly bring scientists and students up to speed with the state of the art in an important and rapidly growing field. Second, to place contemporary methodologies in their proper perspective by including critical evaluations of their real value. And finally, to project promising new directions for the future. To assist investigators in asking precise questions about complex phenomena, the chapter authors endeavor to convey balanced opinions about the various methods.
The genetic dissection of complex traits is a challenge to the practitioners who seek to uncover the genetic architecture underlying complex phenotypes, as well as to those who advocate specific approaches and methodologies. Now that even well-designed and thoughtful investigations are beginning to produce ambiguous results, we are coming to realize that unanticipated challenges underlie what were considered hitherto to be very pomising approaches. Thus we need new strategies, as well as a dose of humility, as we apply them thoughtfully in ways that anticipate failures and frustrations.
This book contains 32 chapters, divided into nine sections, and an appendix. It fills an important void by including a comprehensive account of contemporary methods and a detailed overview of current methodological trends. Section 1, which summarizes briefly Newton Morton's impact on science, is supplemented by a complete list of his research contributions in the appendix. In Section 2 we provide an overview of the methods for genetic dissection of complex traits and a succinct summary of the fundamental concepts of heritability, linkage, and association. In Section 3 we cover phenotypic and genotypic issues, such as quality and refinement, and discuss ways of handling multivariate phenotypes. In Section 4 we discuss the most powerful model-based methodology for linkage analysis, including a critical discussion of its strengths and weaknesses. In Section 5 we present contemporary and promising model-free methods, including variance components methods and transmission disequilibrium tests (TDT). Section 6 presents a comprehensive discussion of emerging new methodologies with considerable potential, including meta-analysis, classification methods, neural networks, and genome partitioning methods. In Section 7 we discuss optimum strategies for mapping complex trait loci, including gene-gene and gene-environment interactions, and special studies of population isolates. In Section 8 we deal with the thorny issues of multiple comparisons and significance levels. Finally, in Section 9 we offer some thoughts for the new millennium.
This book can be used as a handbook for a wide audience of pre- and postdoctoral scientists, methodologists who seek an overview of some of the latest thinking in this area, and, most importantly, the scores of investigators who seek to evaluate the etiological basis of complex traits. It can be used as a reference book for upper-level undergraduate students, as well as a textbook for graduate students majoring in quantitative aspects of human genetics or in genetic epidemiology. It also provides an excellent account for statisticians interested in methodological opportunities. We believe that it represents an important resource that will have some longevity as we march forward in the new millennium.
As the saying goes, "Wisdom comes from experience, and experience comes from making mistakes." Surely we have all made our share of mistakes, hence are experienced, and may now hope that wisdom is just waiting for us to claim it! We have tried to fill this volume with the wisdom the authors have accumulated from their combined experience. Perhaps the most important sign of wisdom is the humility with which we recognize the limitations of some of our current approaches. Predicting the future is a perilous exercise, especially when it comes to complex traits. It is nearly impossible for us to know today which methods will have been the most useful in dissecting the genetic architecture of complex traits when we look back 10 to 20 years from now. We can only judge what appear to be the most promising approaches from our current perspective, and that is what we have tried to document here. No doubt there will be many surprises ahead. Genetic dissection of complex traits is the greatest challenge in genetics at the start of the new millennium, and we hope that the wisdom conveyed herein will shed some light. What a time it is to be a genetic epidemiologist!