Current mechanisms for using sequencing to identify rare variants underlying or co-located with GWA-defined associations include sequencing in genomic regions defined by strong and repeatedly replicated associations with common variants, and sequencing a larger fraction of the genome in people with extreme phenotypes. In the absence of GWA-defined signals, sequencing candidate genes in subjects at the extremes of a quantitative trait (such as lipid levels or the age at onset), can identify other associated variants, both common and rare45,46. An important finding from these studies is that much of the information is provided by people at the extremes of trait distributions, who seem to be more likely to carry loss-of-function alleles47.
