Rare variants, common markers: synthetic association and beyond

The phenomenon of synthetic association raises the possibility that common variant genetic markers may be coupled with functional rare variants sufficiently often to allow the rare variants to be tagged by the common ones. Using human exome sequence data from the 1000 Genomes Project, two investigative teams in Group 12 of Genetic Analysis Workshop 17 found that stochastic coupling between rare and common variants does occur, although perhaps not sufficiently often that we can expect common variant signals to reflect synthetic association; other teams considered methods for detecting association using both rare and common variants. Common themes were that synthetic association is more apparent in population strata (ancestral or familial) and that careful selection of the unit of analysis (gene, gene network, or other genomic subset) is likely to be crucial to the discovery of rare variants that contribute to risk of disease.