It is reasonable to assume that allelic architecture (number, type, effect size and frequency of susceptibility variants) may differ across traits, and that missing heritability may take a different form for different diseases19, but at present our understanding is too limited to distinguish these possibilities. Age-related macular degeneration may provide the best example of a common disease in which heritability is substantially explained by a small number of common variants of large effect20, but for other conditions, such as Crohn’s disease, the proportion of heritability explained is not nearly so large despite a much larger number of identified variants21 (Table 1). There are no obvious differences between these two traits in genetic architecture as predicted from clinical and epidemiological data that would explain the differences observed in their allelic architecture. Some apparent differences may simply be due to differences in the stage of investigation across traits. Studies in several conditions have clearly demonstrated that the number of detected variants increases with increasing sample size22–24.
