Research to pursue initial GWA discoveries will include replication studies in the same phenotypes and populations, to ensure the robustness of the findings, and in similar but not identical phenotypes and populations, to extend the findings and increase understanding of their mechanisms and importance (52). Investigation of disease subtypes, such as estrogen receptor–positive versus -negative breast cancer, or young-onset or severely progressive forms of prostate cancer or diabetes, may be of great value in identifying which subgroups of alleles confer the highest risk and which subgroups of persons carry those alleles. Functional studies of highly replicated variants, in experimental models such as knockdown and overexpression studies (9) and in relationship to gene expression, as recently demonstrated for asthma-associated variants in ORMDL3 (62), will help to determine the mechanisms of gene function and how they are perturbed in disease, providing insights into possible preventive or therapeutic strategies.
