Failure of GWA studies to account for this apparent missing heritability has stimulated debate on the utility of these studies, particularly given the enormous financial and scientific investments dedicated to them. The relative merit of this approach has been debated and discussed in greater detail elsewhere (11, 27). The common disease/common variant hypothesis, which states that common complex diseases are attributable to relatively few common genetic variants of moderate effect, has not been supported. Instead, the genetic underpinning of addictions and other complex diseases may be attributed to either multiple common variants, each contributing a very minor role, or multiple rare variants with intermediate to larger effect sizes, for which the resulting odds ratios fail to reach genome-wide statistical significance using attainable sample sizes. In the past few years, GWA studies have been performed on a very large scale, with tens of thousands of samples from multiple independent studies in order to identify the effects of common variants with small effect sizes (29). However, caution needs to be taken to ensure that these large sample sets are not collected at
