As with the rare allele model, infinitesimal effects are also not consistent with a wide range of demographic effects that are indicative of GxE interactions and complex genetic interactions. Prime among these are (i) the pervasiveness of differences in disease risk between geographic areas that are not obviously explained by genetic differentiation, (ii) increasing burden of complex disease in the span of one or two generations (both of these phenomena are obvious upon browsing the CDC website at http://www/cdc/gov for incidence data), and (iii) conditioning of the risk for one disease on another disease in the same individual106,107. This does not counter the existence of thousands of small effect loci affecting each trait or disease risk profile, but it suggests that the narrow-sense genetic effects alone are unlikely to be sufficient explanation. It must be noted that there is very little evidence from GWAS for either GxE or GxG interactions108, but such effects could be mild at the level of individual associations and be below the power of detection.
