Achieving sufficient power to detect rare variant effects (even large ones) is an important consideration in the design of future studies, of endophenotypes or otherwise. Rare variants of known function, such as a protein-truncating stop-gain variant, or an insertion-deletion that displaces a motif within a strong enhancer, can provide directional and biologically plausible tests of association. As Goldman (2014, this issue) suggests, detailed and systematic study of functional rare variants, with follow-up of promising signals in carrier family members, is a way to efficiently obtain many copies of an otherwise rare variant (e.g., see Bevilacqua et al., 2010). Indeed, the longitudinal MTFS cohorts are ideally suited to recruit additional family members in order to replicate promising findings concerning rare variants. The sequencing analyses reported in this special issue only scratched the surface of possibility, and we are already actively expanding that analysis in many ways.
