Editors, reviewers, and readers expect replication as the standard in science (6). The finding of a genetic association in one population with evidence for replication in multiple independent populations provides moderate assurance against false-positive reports and helps to establish the validity of the original finding. In a single experiment, the discovery-replication structure is traditionally embodied in a two-stage design. The CHARGE consortium includes up to five independent replicate samples as well as additional collaborating studies for some phenotype working groups, so that it would have been possible to set up analysis plans within CHARGE to mimic the traditional two-stage design for replication. For instance, the two largest cohorts could have served as the discovery set and the others as the replication set. However, attaining the extremely small p-values expected in GWAS requires large sample sizes. For any phenotype, a prospective meta-analysis of all participating cohorts, with a properly selected level of genome-wide statistical significance to miminize the chance of false positives, is the most powerful approach to finding new genuine associations for genetic loci (25). When findings narrowly miss the
