Contribution of an additive locus to genetic variance when inheritance is multi-factorial with implications on interpretation of GWAS.

Although the effects of linkage disequilibrium (LD) on partition of genetic variance have received attention in quantitative genetics, there has been little discussion on how this phenomenon affects attribution of variance to a given locus. This paper reinforces the point that standard metrics used for assessing the contribution of a locus to variance can be misleading when there is linkage LD and that factors such as distribution of effects and of allelic frequencies over loci, or existence of frequency-dependent effects, play a role as well. An apparently new metric is proposed for measuring how much of the variability is contributed by a locus when LD exists. Effects of intervening factors, such as type and extent of LD, number of loci, distribution of effects, and of allelic frequencies over loci, as well as a model for generating frequency-dependent effects, are illustrated via hypothetical simulation scenarios. Implications on the interpretation of genome-wide association studies (GWAS), as typically carried out in human genetics, where single marker regression and the assumption of a sole quantitative trait locus (QTL) are common, are discussed. It is concluded that the standard attributions to variance contributed by a single QTL from a GWAS analysis may be misleading, conceptually and statistically, when a trait is complex and affected by sets of many genes in linkage disequilibrium. Yet another factor to consider in the "missing heritability" saga?.