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Epistasis: too often neglected in complex trait studies?

Nature Reviews Genetics volume 5, pages 618–625 (2004)Cite this article

Abstract

Interactions among loci or between genes and environmental factors make a substantial contribution to variation in complex traits such as disease susceptibility. Nonetheless, many studies that attempt to identify the genetic basis of complex traits ignore the possibility that loci interact. We argue that epistasis should be accounted for in complex trait studies; we critically assess current study designs for detecting epistasis and discuss how these might be adapted for use in additional populations, including humans.

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Figure 1: Principles of individual quantitative trait loci and epistatic quantitative trait locus mapping.
Figure 2: Comparing the results of searches for epistatic and individual quantitative trait loci.
Figure 3: Proposed framework for acquiring confidence in quantitative trait loci.

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Acknowledgements

We are grateful to the Biotechnology and Biological Sciences Research Council and to the Knut and Alice Wallenberg Foundation for their support. We thank B. Hill, G. Plastow, J. Cheverud and two anonymous referees for some valuable comments on the manuscript and A. Peripato for helpful assistance with providing data.

Author information

Authors and Affiliations

  1. Linnaeus Centre for Bioinformatics, Uppsala University, BMC, Box 598, Uppsala, SE-751 24, Sweden

    Örjan Carlborg

  2. Department of Genetics and Biometry, Roslin Institute, Roslin, Midlothian, EH25 9PS, UK

    Chris S. Haley

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  1. Örjan Carlborg
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Corresponding author

Correspondence to Örjan Carlborg.

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Related links

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DATABASES

Entrez

ACE

AGTR1

KIT

MC1R

OMIM

type I diabetes

type II diabetes

FURTHER INFORMATION

Örjan Carlborg's web page

The Roslin Institute

Glossary

ASSOCIATION STUDIES

A set of methods that is used to identify correlations between genetic polymorphisms and expression of phenotypes, such as diseases, in populations.

BOMBAY PHENOTYPE

A rare ABO blood group (Oh) in which the genotype at a locus other than the ABO gene locus makes the individuals seem to have blood type 'O' even if the 'A' or 'B' enzymes are present.

CANDIDATE GENES

Genes in which functional variation is thought to affect the trait under consideration, often on the basis of their physiological role or their effects in other species.

F-PROFILE

A plot of the statistical support (measured by an F-test) for quantitative trait loci at regular intervals throughout the genome.

FALSE DISCOVERY RATE

(FDR). The proportion of false-positive test results out of all positive (significant) tests (note that the FDR is conceptually different to the significance level).

FIRST-ORDER GENETIC INTERACTIONS

Interactions between pairs of genes or quantitative trait loci.

FORWARD SELECTION

A statistical procedure in which a multi-dimensional genome scan is reduced to a series of sequential one-dimensional genome scans.

HAPLOTYPE

The allelic configuration of multiple genetic markers that are present on a single chromosome of a given individual.

MAJOR GENE

A gene that is part of a polygenic or oligogenic system but for which alternative alleles have a large influence on the phenotype.

MARKER-ASSISTED SELECTION

(MAS). Genetic markers are used to indirectly select for specific alleles at closely linked trait loci by directly selecting for the marker.

PENETRANCE

The proportion of individuals with a specific genotype who manifest the genotype at the phenotypic level. For example, if all individuals with a specific disease genotype show the disease phenotype, then the disease is said to be 'completely penetrant'.

QUANTITATIVE TRAIT

A continuously distributed measurable trait for which variation depends on a single gene or on the cumulative action of many genes and the environment. Common examples include height, weight and blood pressure.

QUANTITATIVE TRAIT LOCUS

(QTL). Genetic loci or chromosomal regions that contribute to variability in complex quantitative traits, as identified by statistical analysis. Quantitative traits are typically affected by several genes and by the environment.

RANDOMIZATION TEST

A statistical test in which statistical significance is judged by comparison to a distribution that is generated by repeated random permutations of the actual data.

RECOMBINANT INBRED LINE

A population of fully homozygous individuals that is obtained by repeated selfing from an F1 hybrid, and that comprises 50% of each parental genome in different combinations.

SIMULTANEOUS SCAN

A multi-dimensional genome scan in which several gene locations are selected simultaneously.

VARIANCE-COMPONENT APPROACH

Quantitative trait locus (QTL) analysis method, suited to complex family structures, in which variance that is attributable to a QTL is estimated rather than the mean effects of alternative genotypes.

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Carlborg, Ö., Haley, C. Epistasis: too often neglected in complex trait studies?. Nat Rev Genet 5, 618–625 (2004). https://doi.org/10.1038/nrg1407

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