There remain two key questions. First, is there a long tail of low OR associations still to be found? Second, are there, as might be expected, different associations in non-European populations? The lower the OR, the larger the study needed to achieve statistical significance and the harder it will be to find an association against a background of inevitably increased environmental, and possibly ethnic, heterogeneity. There is a sort of uncertainty principle here, as variant effects merge into the effects of a variable background environment. Given the difficulty of applying even those results associated with larger ORs, it is a serious question as to whether it is cost effective to do larger and larger studies simply to try and find out in more detail the population specific genetic architecture of a disease. Genotype by environmental effects will only be found by very large WGAS in different well-controlled environments that are not confounded by ethnic differences. It may well be questioned whether such studies are, in general, even possible, let alone worthwhile. It must be expected that the smaller the OR, the more likely it will be that environmental factors predominate.
