Invited Review

Non-Replication and Inconsistency in the Genome-Wide Association Setting
John P.A. Ioannidis

Clinical and Molecular Epidemiology Unit and Evidence-Based Medicine and Clinical Trials Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Biomedical Research Institute-Foundation for Research and Technology-Hellas, Ioannina, Greece; Department of Medicine, Tufts University School of Medicine, Boston, Mass.., USA

Address of Corresponding Author

Hum Hered 2007;64:203-213 (DOI: 10.1159/000103512)

  Key Words

• Replication
• Heterogeneity
• Inconsistency
• Bias
• Genome-wide association
• Gene
• Polymorphism

  Abstract

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.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

Prof. John P.A. Ioannidis, Chairman
Department of Hygiene and Epidemiology
University of Ioannina School of Medicine
GR-45110 Ioannina (Greece)
Tel. +30 265 109 7807, Fax +30 265 109 7867, E-Mail jioannid@cc.uoi.gr

  Article Information

Received: February 5, 2007
Accepted after revision: April 4, 2007
Published online: June 6, 2007
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 3, Number of References : 87