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The complex interplay among factors that influence allelic association

Nature Reviews Genetics volume 5, pages 89–100 (2004)Cite this article

An Erratum to this article was published on 01 March 2004

Key Points

  • Although complex gene studies are typically designed by focusing on such factors as linkage disequilibrium (LD) or the frequency of the susceptibility loci, the interplay between such factors is much more important than their isolated effects. The joint effects of marker allele frequency, linkage disequilibrium and allelic effect size are crucial in determining the statistical power to detect associations between complex traits and candidate genes in well-designed, population-based case–control studies.

  • The relationship between these parameters can be quantitatively described and various situations of interplay should be considered in the design stage of case–control studies.

  • Provided large sample sizes are used, common (>0.1 in frequency) markers in high LD with either common disease alleles of small effect or rare disease alleles of large effect should generally be suitable to detect association with loci of moderate effect sizes, as long as multiple rare alleles of equal effect size do not cancel each other out by being associated with opposite marker alleles.

Abstract

Small effect sizes, common-disease/common-variant versus rare variant influences, biased single nucleotide polymorphism ascertainment and low linkage disequilibrium have recently been discussed as impediments to association studies. Such a focus on the individual factors that highlight their maximum potential effect (whether positive or deleterious) is often optimistic as, in practice, they do not operate in isolation. Instead, they work jointly to generate the disease gene architecture and to determine the ability of a study to discover it. Here, we consider how the effect size of the susceptibility locus, the frequency of the disease allele(s), the frequency of the marker allele(s) that are correlated with the disease allele(s) and the extent of linkage disequilibrium together influence genetic association studies.

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Figure 1: Reduction in effect size owing to linkage disequilibrium and mismatches between marker and disease allele frequencies.
Figure 2: The joint influence of linkage disequilibrium, effect size and marker–disease allele frequencies on the power to detect disease association.

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Acknowledgements

We thank A. Morris for his very helpful comments on several of the ideas underlying this paper, and J. Marchini for help with some of the data representations. This work was supported by a Wellcome Trust Principal Research Fellowship to L.R.C. and a Medical Research Council Fellowship in Bioinformatics to K.T.Z.

Author information

Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Krina T. Zondervan & Lon R. Cardon

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Correspondence to Lon R. Cardon.

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Related links

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DATABASES

Entrez

APOE( * 4)

factor V Leiden

GSTM1

NOD2/CARD15

PPARγ

OMIM

Alzheimer disease

bladder cancer

Crohn disease

deep vein thrombosis

type II diabetes

FURTHER INFORMATION

International HapMap Project

Glossary

COMPLEX TRAIT

A measured phenotype, such as disease status or a quantitative character, which is influenced by many environmental and genetic factors, and potentially by interactions in and between them.

EFFECT SIZE

The extent to which a factor influences the risk of the condition under study, rather than simply an indication of whether a factor is significantly related to the condition.

LINKAGE DISEQUILIBRIUM

Two loci that are in linkage disequilibrium are inherited together more often than would be expected by chance.

MULTIFACTORIAL DISEASE

A disease that is influenced by many environmental and genetic susceptibility factors (see also complex trait).

HAPLOTYPE TAGGING

The concept that most of the haplotype structure (allele combination) in a particular chromosomal region can be captured by genotyping a smaller number of markers than all of those that constitute the haplotypes. The crucial markers to type would be those that distinguish one haplotype from another.

CASE–CONTROL STUDY

An epidemiological study design in which cases with a defined condition and controls without this condition are sampled from the same population. Risk-factor information is compared between the two groups to investigate the potential role of these in the aetiology of the condition.

EPIDEMIOLOGY

A discipline that seeks to explain the extent to which factors to which people are exposed (environmental or genetic) influence their risk of disease, by means of population-based investigations. Epidemiological studies are designed to minimize bias in obtaining results for the population under study.

POWER

The probability of a study to obtain a significant result if this result is true in the underlying population from which the study subjects were sampled.

PROSPECTIVE COHORT STUDY

Longitudinal analysis in which individuals selected for certain exposure characteristics are followed up over time to assess who develops a certain outcome (often disease).

GENOMIC CONTROL

Statistical/genetic procedure in which the apparent association between a particular polymorphism and a certain condition is adjusted for population stratification in the study sample using a set of randomly selected, unlinked markers. Population stratification can occur if the study sample consists of two or more sub-populations with distinct differences in allele frequencies.

INCOMPLETE PENETRANCE

A situation in which the probability of having the disease, given that one has the disease mutation(s), is less than 1.0.

HAPLOTYPE PHASE

The arrangement of alleles at two loci on homologous chromosomes. For example, in a diploid individual with genotype Mm at a marker locus and genotype Aa at the other locus, possible linkage phases are MA/ma and Ma/mA, for which '/' separates the two homologous chromosomes.

MINOR ALLELE FREQUENCY

The lowest allele frequency at a locus that is observed in a particular population. For single nucleotide polymorphisms, this is simply the lesser of the two allele frequencies.

MICROSATELLITE

A class of repetitive DNA sequences that are made up of tandemly organized repeats that are 2–8 nucleotides in length. They can be highly polymorphic and are frequently used as molecular markers in population genetics studies.

GENETIC DRIFT

The random fluctuation in population allele frequencies as genes are transmitted from one generation to the next.

TYPE I ERROR

The probability of rejecting the null hypothesis when it is true. For genetic association studies, type I errors reflect false-positive findings of associations between allele/genotype and disease.

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Zondervan, K., Cardon, L. The complex interplay among factors that influence allelic association. Nat Rev Genet 5, 89–100 (2004). https://doi.org/10.1038/nrg1270

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