Of these possible settings, the one receiving the most attention by statistical geneticists is the ‘extreme allelic heterogeneity (EAH)’ setting in which single or small subgroups of individuals with a particular phenotype or disease possess any one, or some subset, of a larger set of rare variants that all independently perturb a single relevant gene in a similar way.12, 31 Although conceptually easier to accommodate in statistical analysis models, there is no reason to believe that the EAH setting is the rule rather than the exception with respect to rare variant influences on phenotypic expression. Statistical analysis models and methods for rare variant association studies should therefore be developed and tested in settings that go beyond the EAH model, such as settings implicating synergistic effects of rare (and common) variants within (and across) genomic regions.
