One objection to this argument is that we do not know how to predict the genetic architecture of a phenotype prior to genetic mapping. Just because a phenotype qualifies as intermediate does not guarantee that it has a more tractable genetic architecture to disease. It was not clear a priori why genetic analysis of Crohn’s disease would require a few thousand cases, whereas breast, prostate and colorectal cancers required much larger samples [44]. Heritability is not a useful guide (as the example of height indicates [45]). Supposed proximity to the underlying biology (and therefore site of genetic action), while an attractive concept, has not turned out to have much predictive value. This remains an area where we must be guided by empirical findings from GWAS.
