There are several important corollaries. Notwithstanding the incomplete coverage afforded by the genotyping reagents employed, most of the susceptibility effects yet to be uncovered for these diseases (at least those attributable to, or tagged by, common SNPs) are likely to have effects of similar or smaller magnitude to those we have highlighted. Beyond the signals with the strongest evidence for association, most of which are likely to be real (and many of which have already been confirmed), there will be many additional susceptibility variants for which the WTCCC provides some evidence, but for which extensive replication will be required to establish validity. PPARG and KCNJ11 provide examples of proven susceptibility genes (for T2D) that generated only modest evidence for association within the WTCCC, and which would only have been revealed by such replication efforts. Given the likely preponderance of susceptibility variants of small effect, the potential for identifying further loci is limited only by the clinical resources available for replication (assuming suitable study design, accurate genotyping and appropriate analysis and inference). Provided the attribution of a causal relationship with the trait of interest is robust, even variants of very small effect can offer fundamental biological insights.
