Detecting epistasis in human complex traits

Tremendous activity in the development of methodology has now rendered the exhaustive search for pairwise genetic interactions computationally routine, but addressing the statistical problems of detecting epistasis remains a big challenge.Most reports of epistasis influencing human complex traits that exist in the literature raise concerns regarding their validity and do not follow the same strict protocols that are in place for reporting additive effects.There is mounting evidence against the existence of pairwise epistatic effects influencing human complex traits that are sufficiently large for detection in standard single-sample genome-wide association studies (GWASs). If epistatic effects do influence complex traits, then each interaction effect will probably be small, as is observed with additive effects.The majority of robust additive effects are only found when GWASs are carried out using huge sample sizes and good single-nucleotide polymorphism coverage, often as a result of multistudy meta-analyses. Similar approaches are necessary if epistatic effects are also to be robustly detected, although methodology or attempts at implementation are yet to surface.Methods have emerged for estimating the total contribution of additive effects across the whole genome; similar methods for estimating the total contribution of genetic interactions would be valuable but have not yet been developed.