The ability of GWA meta-analyses to identify rare associated variants can be improved with imputation (61). The development of methods for imputing markers from fully genotyped reference panels into phenotyped samples with GWA markers has improved the genomic coverage, and therefore power of GWA meta-analyses. However, there are many more rare variants in the genome than common variants, and these variants typically have fewer highly correlated proxies. This makes rare variants much more difficult to impute from GWA marker panels. Methods for estimating the accuracy of imputed markers are also somewhat less informative for rare variants than for common. However, in spite of these limitations, preliminary imputation experiments have shown that rare variants can be imputed and may play at least some role in common diseases (65).
