Abstract
Genome-wide associations have shown a lot of promise in dissecting the genetics of complex traits in humans with single variants, yet a large fraction of the genetic effects is still unaccounted for. Analyzing genetic interactions between variants (epistasis) is one of the potential ways forward. We investigated the abundance and functional impact of a specific type of epistasis, namely the interaction between regulatory and protein-coding variants. Using genotype and gene expression data from the 210 unrelated individuals of the original four HapMap populations, we have explored the combined effects of regulatory and protein-coding single nucleotide polymorphisms (SNPs). We predict that about 18% (1,502 out of 8,233 nsSNPs) of protein-coding variants are differentially expressed among individuals and demonstrate that regulatory variants can modify the functional effect of a coding variant in
cis
. Furthermore, we show that such interactions in
cis
can affect the expression of downstream targets of the gene containing the protein-coding SNP. In this way, a
cis
interaction between regulatory and protein-coding variants has a
trans
impact on gene expression. Given the abundance of both types of variants in human populations, we propose that joint consideration of regulatory and protein-coding variants may reveal additional genetic effects underlying complex traits and disease and may shed light on causes of differential penetrance of known disease variants.
The ultimate goal of genome-wide association studies (GWAS) is to explain the proportion of variation in a phenotypic trait that can be attributed to genetic factors. The past two years have seen a plethora of successes in this field, yet, for most traits, a large fraction of variation remains unexplained. Epistasis, or interaction between genetic variants, is a largely under-explored factor, which may shed some light in this area. We use the HapMap populations to investigate interactions between regulatory and protein-coding variants and their impact on gene expression. We show that if a specific protein-coding variant has a functional impact, this can be modified by a co-segregating regulatory variant (
cis
interaction). Furthermore, the authors demonstrate that such modification effects between variants at one locus may affect the expression of other genes in the cell in a
trans
manner. The aim of this article is to present a framework though which variation can be considered in the context of GWAS. Viewing variation from this underappreciated angle may, in some cases, provide an explanation for differential penetrance of complex disease traits, but also for non-replication of GWAS results that may arise as a consequence of such interactions.