Chunk #96 — 7.0 Recommendations to Advance Endophenotype Genetics — 7.3 Adequate power to detect individual effects is crucial but almost never attained in existing endophenotype genetic association studies — 7.3.1. Power and sampling schemes in GWAS
One can imagine exceptions to our general conclusion, but these exceptions are not observed in the current literature. For example, some rare variant may have a large effect on the phenotype, such that carrying it greatly increases one's risk for disease or score on a disease-related endophenotype. In a community representative sample, or a sample selected on the basis of phenotype, the rare variant will only affect risk in the few carriers who harbor it, and statistical power to detect the effect will remain low (because VX is necessarily low due to low minor allele frequency [MAF]). However, if one selects participants based on genotype or ancestry, such that carriers of the rare variant are oversampled, the MAF of the variant in the sample and thus statistical power can be greatly increased. This kind of study design has traditionally involved large pedigrees with high incidence of disorder. Classic examples include the first report of linkage in Huntington's disease (Gusella et al., 1983) and even the Sherrington et al paper (Sherrington et al., 1988) described at the outset of this article.
