One major hurdle in rare variant association analysis is statistical power—rare variants may have very large effects but still account for tiny fractions of population disease burden. For example, recent research has identified rare variants affecting macular degeneration with odds ratios of 20:1 (Raychaudhuri et al., 2011) and similarly large effects on other diseases (Cohen & Hobbs, 2013; Sigma Type 2 Diabetes Consortium et al., 2014; TG and HDL Working Group of the Exome Sequencing Project, 2014). However, even a completely penetrant rare variant can only account for a tiny fraction of disease burden, because it affects so few people. Cardiovascular disease causes over half a million deaths annually, but a rare variant present in only 1 in 10,000 individuals can only be responsible for 50 of those deaths. For analogous reasons, any individual rare variant cannot account for substantial heritability in any given population, even with a huge effect size (yet another way that heritabilities are unreliable guides in the discovery of gene associations).
