Non-replication and inconsistency in the genome-wide association setting.
Non-replication and inconsistency had been common features in the search for common variants of candidate genes affecting the risk of complex diseases. They may continue to require attention in the current era, when massive hypothesis-free testing of genetic variants is feasible. An empirical evaluation of the early experience with genome-wide association (GWA) studies suggests several examples where proposed associations have failed to be replicated by subsequent investigations. Non-replication and inconsistency is defined here in the framework of cumulative meta-analysis. Ideally, associations exist, GWA finds them, and subsequent investigations should replicate them. However, a number of other possibilities need to be considered. No common genetic variants may associate with the phenotype of interest and GWA may find nothing; or associations may exist, but GWA may miss them. Associations that do not exist may be falsely selected by the GWA and subsequent studies may appropriately refute them or falsely replicate them. Finally, GWA may find true associations that are nevertheless falsely non-replicated in the subsequent studies; or associations may be genuinely inconsistent across study populations. A list of options is presented for consideration in each of these scenarios.
Ioannidis
John P A
JP
Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Biomedical Research Institute-Foundation for Research and Technology-Hellas, Ioannina, Greece. jioannid@cc.uoi.gr
D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D015201:Meta-Analysis as Topic; D010641:Phenotype; D011110:Polymorphism, Genetic