When GWA studies were first introduced in the field of genetic research of complex diseases their premise and method were simple; screen for association using markers spaced evenly across the genome to capture the effects of most, if not all, the common genetic variation in any individual, determine their associations with phenotypes of interest, and assess these loci for their functional effects in relation to disease process. However, some major challenges rapidly arose. The common alleles examined in these studies account for relatively small increments in risk and explain only a minor proportion of the phenotypic variance observed, with the odd ratios of associated SNPs in the range of 1.1 ~ 2.0 (27). Much of the genetic variance for a number of complex traits has not been accounted for; human height is one example, with an estimated heritability of ~80%, but only ~6% of the phenotypic variance accounted for by GWA studies (27). A similar observation was made for nicotine addiction; the proportion of variance in cigarette consumption accounted for by markers identified in GWA studies only ranges from ~1%
