The predictive accuracies mentioned in the previous section are all based on replicated risk variants discovered by GWAS to date. However, established GWAS loci typically explain only a small fraction of the heritability of complex diseases [an observation known as ‘missing heritability’ (27)]. Regardless of the explanation for this phenomenon, it raises questions about broader methods of risk prediction using the entire genome. A number of approaches have been developed to address this issue, but the answers they provide depend on the assumptions inherent in different models of as-yet undiscovered genetic risk.
