Inevitably an increase in sample size achieved by pooling samples across studies introduces phenotype heterogeneity that may alter the power to discover genes or G*E interactions for a complex trait of interest. During gene discovery, the balance between power achieved by larger sample size versus loss of power produced by introduced phenotype heterogeneity during phenotype harmonization may favor the former. For example, little is known about the genetic architecture of primary open-angle glaucoma (POAG) although the sib relative risk is 10 [Wolfs et al., 1998]. Icelandic investigators reported two SNPs between CAV1 and CAV2 associated with POAG with an OR of ∼1.3 and with a p-value of 5E-10 [Thorleifsson et al., 2010]. Several replication datasets were provided and phenotype definitions varied widely. Not all replication sets achieved statistical significance and several had wide confidence intervals. When the replication sets were combined they did achieve significance with an effect size and confidence comparable to that reported in the discovery set. This suggests that the association between CAV1 and CAV2 gene variants and POAG represents a true positive and that pooling samples
