Although there are a number of ways to leverage functional annotations to guide the collapsing of rare variants in association studies, their use will only be as good as the science behind those annotations. It is also possible that different functional ‘levels’ of annotation can be used to define collapsed sets of rare variants. For example, one could define a set of variants as ‘genic’ if they reside in the open reading frame associated with a gene; as ‘exonic’ if they reside in coding regions within that frame; as ‘non-synonymous coding variants’ if they perturb an encoded amino acid; and as ‘non-synonymous coding within an active site of the encoded protein’ if a variant impacts a residue within the active site of the encoded protein. With this in mind, one could perhaps test hierarchies of hypotheses about collections of variants and their biological impact on a phenotype.
