Two-stage two-locus models in genome-wide association - PubMed (original) (raw)

Two-stage two-locus models in genome-wide association

David M Evans et al. PLoS Genet. 2006.

Abstract

Studies in model organisms suggest that epistasis may play an important role in the etiology of complex diseases and traits in humans. With the era of large-scale genome-wide association studies fast approaching, it is important to quantify whether it will be possible to detect interacting loci using realistic sample sizes in humans and to what extent undetected epistasis will adversely affect power to detect association when single-locus approaches are employed. We therefore investigated the power to detect association for an extensive range of two-locus quantitative trait models that incorporated varying degrees of epistasis. We compared the power to detect association using a single-locus model that ignored interaction effects, a full two-locus model that allowed for interactions, and, most important, two two-stage strategies whereby a subset of loci initially identified using single-locus tests were analyzed using the full two-locus model. Despite the penalty introduced by multiple testing, fitting the full two-locus model performed better than single-locus tests for many of the situations considered, particularly when compared with attempts to detect both individual loci. Using a two-stage strategy reduced the computational burden associated with performing an exhaustive two-locus search across the genome but was not as powerful as the exhaustive search when loci interacted. Two-stage approaches also increased the risk of missing interacting loci that contributed little effect at the margins. Based on our extensive simulations, our results suggest that an exhaustive search involving all pairwise combinations of markers across the genome might provide a useful complement to single-locus scans in identifying interacting loci that contribute to moderate proportions of the phenotypic variance.

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Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Power to Detect Association for 1,500 Individuals where Both Loci Are Responsible for 5% of the Trait Variance

Power is displayed on the vertical axis, allele frequencies at both loci on the horizontal axes. Results are shown for an (A) additive model where there is no epistasis (MA), (B) a simple looking epistatic model (M27) in which an individual requires at least one copy of the increaser allele at both loci in order to increase the quantitative phenotype above baseline levels, and (C) a more exotic model where an individual has to be heterozygous at both loci in order to have a trait mean above baseline (M16).

Figure 2

Figure 2. Partitioning of the Variance for Four Quantitative Trait Models

(A) Expected variance components at locus 1, locus 2, and the epistatic variance component for model M27 in which an individual requires at least one copy of the increaser allele at both loci in order to increase the quantitative phenotype above baseline levels. Note in particular that when alleles “A” and “B” are common at both loci, the majority of genetic variance resides in the epistatic component. (B) The proportion of the total genetic variance which is due to statistical epistasis for three simple models. The vertical axis denotes the proportion of variance, whereas the horizontal axes denote allele frequencies at each locus. For each model, the epistatic variance component is appreciable for a sizeable portion of the space of possible allele frequencies.

Figure 3

Figure 3. Power Associated with the Two-Stage Strategies in the Case of Two Loci Responsible for 5% of the Trait Variance Generated under Model M27 in which an Individual Requires at Least One Copy of the Increaser Allele at Both Loci in Order to Increase the Quantitative Phenotype above Baseline Levels as Applied to 1,000 Individuals

Five different first-stage thresholds are shown. In the case of the Both Significant Two-Stage Strategy, there is a rapid decrease in power with increasingly stringent first-stage thresholds, except for a small proportion of the space of possible allele frequencies where there is a small gain in power. In the case of the Either Significant Strategy, power declines more slowly as the first-stage threshold becomes increasingly stringent.

Figure 4

Figure 4. Fifty-One Biallelic Two-locus Models Incorporating Varying Degrees of Epistasis

Each row indexes the genotype at the first locus and each column refers to the genotype at the second locus. The number in each cell is the trait mean for that genotype. Models range from the very simple (e.g., M1) to the more exotic (e.g., M170).

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