Hum Hered 2003;56:73–82

The Ubiquitous Nature of Epistasis in Determining Susceptibility to Common Human Diseases

Moore J.H.
Program in Human Genetics, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, Tenn., USA
email Corresponding Author

 goto top of outline Key Words

  • Gene-gene interactions
  • Multifactor dimensionality reduction
  • Biological systems moduling

 goto top of outline Abstract

There is increasing awareness that epistasis or gene-gene interaction plays a role in susceptibility to common human diseases. In this paper, we formulate a working hypothesis that epistasis is a ubiquitous component of the genetic architecture of common human diseases and that complex interactions are more important than the independent main effects of any one susceptibility gene. This working hypothesis is based on several bodies of evidence. First, the idea that epistasis is important is not new. In fact, the recognition that deviations from Mendelian ratios are due to interactions between genes has been around for nearly 100 years. Second, the ubiquity of biomolecular interactions in gene regulation and biochemical and metabolic systems suggest that relationship between DNA sequence variations and clinical endpoints is likely to involve gene-gene interactions. Third, positive results from studies of single polymorphisms typically do not replicate across independent samples. This is true for both linkage and association studies. Fourth, gene-gene interactions are commonly found when properly investigated. We review each of these points and then review an analytical strategy called multifactor dimensionality reduction for detecting epistasis. We end with ideas of how hypotheses about biological epistasis can be generated from statistical evidence using biochemical systems models. If this working hypothesis is true, it suggests that we need a research strategy for identifying common disease susceptibility genes that embraces, rather than ignores, the complexity of the genotype to phenotype relationship.

Copyright © 2003 S. Karger AG, Basel

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 goto top of outline Author Contacts

Jason H. Moore, PhD
Program in Human Genetics, Department of Molecular Physiology and Biophysics
519 Light Hall, Vanderbilt University Medical School
Nashville, TN 37232-0700 (USA)
Tel. +1 615 343 5852, Fax +1 615 343 8619, E-Mail

 goto top of outline Article Information

Received: April 22, 2003
Accepted after revision: June 17, 2003
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 0, Number of References : 68

 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)
Founded 1950 as Acta Genetica et Statistica Medica by Gunnar Dahlberg; Continued by M. Hauge (1965–1983)

Vol. 56, No. 1-3, Year 2003 (Cover Date: Released November 2003)

Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)

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