One method for reducing the inclusion of the noise variants would be to increase the size of the score “discovery” sample, similar to the rapidly increasing sample sizes utilized in genome-wide association studies (GWAS; Amin et al., 2009). However, increasing sample size may not be practical for certain phenotypes that are rare, or for those that require thorough assessment or selected samples. In such cases, alternatives to atheoretical genome-wide approaches are needed, in order to take into account the reduced statistical power inherent in genetic analyses of smaller samples. With this in mind, we suggest one possible approach to improving the accuracy of the genetic risk score: reducing the “noise” variants available for inclusion by only examining genes located within a candidate system (i.e., genomic regions specifically theorized to be involved with one or more processes that influence the phenotype of interest).
