The wide spectrum of AUC values shown in Figure 1 is attributable to a number of factors. Sample size and study design (such as the ‘three stage’ designs used in several cancer studies) play important roles in the process of variant discovery which feeds into risk prediction. Clinical heterogeneity and the complexity of affected tissues likely contribute to the recalcitrance of psychiatric illness to genetic prediction (and GWAS more generally). Highly heritable diseases are unsurprisingly usually easier to predict [a review of heritabilities is in Wray et al. (23)]. These principles are exemplified in Crohn's disease, which has been subject to large GWAS, is more heritable than the etiologically similar (but harder to predict) ulcerative colitis and has a definitive clinical diagnosis. Other differences are harder to explain using any of these arguments, such as the significantly greater predictive accuracy of type 2 diabetes compared with coronary artery disease, which is more heritable and has been subjected to larger GWAS meta-analyses.
