receptors in congestive heart failure (31)], although they have not been replicated. However, this phenomenon has not been thoroughly explored through large-scale analysis of genome-wide SNP interactions, first due to the fact that current sample sizes are underpowered to detect modest interaction effects and secondly due to the paucity of sample collections with genetic and detailed environmental exposure data. Complex patterns of inheritance, such as parent of origin effects (32), as well as inherited epigenetic modifications of the genome, the presence of phenotype heterogeneity in the cohorts used in the first wave of GWAS, or even an initial over-estimation of the heritability of complex traits (33) can also contribute to the missing heritability.
