Supplemental Material for de los Campos, Sorensen and Toro, 2019
dataset
posted on 2019-03-27, 14:38 authored by Gustavo de los Campos, Daniel A. Sorensen, Miguel A. ToroThe genetic architecture of complex
human traits and diseases is affected by large number of possibly interacting
genes, but detecting epistatic interactions can be challenging. In the last
decade, several studies have alluded to problems that linkage disequilibrium
can create when testing for epistatic interactions between DNA markers.
However, these problems have not been formalized nor have their consequences
been quantified in a precise manner. Here we use a conceptually simple three
locus model involving a causal locus and two markers to show that imperfect LD
can generate the illusion of epistasis, even when the underlying genetic
architecture is purely additive. We describe necessary conditions for such “phantom epistasis” to emerge and
quantify its relevance using simulations. Our empirical results demonstrate
that phantom epistasis can be a very serious problem in GWAS studies (with
rejection rates against the additive model greater than 0.28 for nominal
p-values of 0.05, even when the model is purely additive). Some studies have sought
to avoid this problem by only testing interactions between SNPs with R-sq.
<0.1. We show that this threshold is not appropriate and demonstrate that
the magnitude of the problem is even greater with large sample size,
intermediate allele frequencies, and when the causal locus explains a large
amount of phenotypic variance. We conclude that caution must be exercised when
interpreting GWAS results derived from very large data sets showing strong
evidence in support of epistatic interactions between markers.