Validating, augmenting and refining genome-wide association signals

Abstract

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.

Figure 1 |. Putting it in order.

The arrows show the flow of research effort and thicker arrows show the more common sequence for the use of these methods. Typically, robust statistical documentation of an association takes precedence over refinement efforts. Otherwise, one runs the risk of spending funds and efforts on associations that are false positives with low yield. After robust exact replication, one can proceed directly to functional evidence if there is an immediately obvious observation (for example, a striking coding change), or wait to perform functional studies only after additional genetic and epidemiological refinement. Genetic and epidemiological refinements typically proceed in parallel. In this process, if definitive genetic or epidemiological evidence arises, one can again proceed with functional assays. Finally, if suitable data are available, phenome mapping can be exploited at different stages: at early stages for maximizing power, and detecting and replicating the strongest associations; or at late stages for assessing the full phenotypic range.