In light of the many difficulties in candidate gene studies as they have typically been conducted, we suggest conducting such studies only when there is compelling evidence supporting a particular gene's candidacy. We suggest a two-dimensional spectrum of acceptability, diagrammed in Figure 3. First, we propose a spectrum of statistical association evidence. On one end are variants that have been indubitably associated with the clinical outcome(s) of interest or the endophenotype of interest. On the other end are variants that have mixed evidence from low-powered non-GWAS studies. The second spectrum concerns whether the variant is predicted to affect a genomic or molecular mechanism. Variants with relatively clear mechanisms (e.g., changes to coding sequence or gene expression) will be easier to interpret and functionally characterize, whereas variants with unclear mechanisms, such as intergenic variants with no functional signatures, may be more difficult to characterize. Variants can be prioritized for follow-up in proportion to the degree of evidence for association. Variants that show strong evidence of association but also implicate a known mechanism should receive highest priority.
