Validating, augmenting and refining genome-wide association signals

Key Points Genome-wide association studies have yielded a large number of association signals with robust statistical support, but these are only markers of the true functional variants. Reliable identification of the true functional variants can be notoriously difficult, but a series of methods could be helpful in this regard. Large-scale exact replication to achieve robust statistical credibility of a marker should precede efforts at finding the causative variants. Fine mapping and resequencing might help to identify more informative markers and multiple independent informative loci. Functional information could fine tune the credibility of different variants for being the causative variant. Additional insights might be obtained by more extensive phenotype mapping of proposed variants. Genome-wide association studies have identified many promising links between genetic variants and human traits. However, the steps from the initial identification of associated markers to the reliable validation of the causal variant are long and tortuous, as the authors describe. 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.