Chunk #97 — 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
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. Novel designs to sample rare variant carriers are now possible with the advent of large-scale biobanks (e.g., The Nord-Trøndelag Health Study HUNT Biobank, the UK Biobank, Million Veterans Program, and many others) from which individuals could be selected on the basis of their (rare) genotype and perhaps augmented with family members not already in the biobank but who are also likely to carry the rare allele of interest. This novel selection strategy, and many others that will be possible with population-level sequencing, may be leveraged to greatly increase variance in the predictor (VX) by increasing the MAF of the genetic variant, thereby increasing power for testing association. Keep in mind, however, that this entire strategy depends on knowing which rare variants are important, out of the many hundreds of millions of rare variants that exist. We have argued in this section that GWAS is one recommended way to determine which genomic regions, or loci, contain genetic variants that influence risk
