The second assumption is that once genetic loci contributing to the intermediate phenotype have been found, this will facilitate the search for disease susceptibility loci. For instance, rather than searching the entire genome for loci associated with the primary phenotype of disease susceptibility, and suffering the penalty of applying a corrected significance threshold of P < 5×10-8 (i.e., genomewide significance), researchers will use a GWAS of the intermediate phenotype to identify putative markers for disease susceptibility. Those few found with reliable evidence in the GWAS of the intermediate phenotype can then be followed up in relation to the primary phenotype to confirm their role in disease susceptibility, requiring an appropriate but far less restrictive multiple comparison correction [20]. In other words, intermediate phenotypes can provide a reduced search space for disease susceptibility loci. We review the evidence for these assumptions in turn.
