As increasing numbers of GWAS were published in 2005-2006, it became apparent that typical sample sizes (e.g., 1,000 cases and 1,000 controls) did not usually lead to associations that exceeded chance levels of significance. Such findings provided, for the first time, evidence that the genetic effect sizes for common variation were considerably smaller than had been appreciated. For example, in the pre-GWAS era, many investigators powered their studies to detect genotypic relative risks of °1.54 (1000 cases/1000 controls, α=5×10-8, and 90% power). Using the NHGRI GWAS catalog (Hindorff, 2009)}, the typical genotypic relative in a GWAS is far smaller than appreciated previously (median of 1.28) which necessitates a sample size of over 3,000 cases and 3,000 controls. To identify the 25th percentile genotypic relative risk of 1.18 requires nearly 7,000 cases and 7,000 controls.
