Validating, augmenting and refining genome-wide association signals.
Studies using genome-wide platforms have yielded an unprecedented number of promising signals of association between genomic variants and human traits. This Review addresses the steps required to validate, augment and refine such signals to identify underlying causal variants for well-defined phenotypes. These steps include: large-scale exact replication across both similar and diverse populations; fine mapping and resequencing; determination of the most informative markers and multiple independent informative loci; incorporation of functional information; and improved phenotype mapping of the implicated genetic effects. Even in cases for which replication proves that an effect exists, confident localization of the causal variant often remains elusive.
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine and Biomedical Research Institute, Foundation for Research and Technology - Hellas, Ioannina 45110, Greece. jioannid@cc.uoi.gr
John P A
JP
Ioannidis
Gilles
G
Thomas
Mark J
MJ
Daly
D000818:Animals; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D016678:Genome; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D010641:Phenotype; D015203:Reproducibility of Results