A further sample size penalty is incurred when we realize that it is unlikely that only one locus will need to be validated: a 5% uncorrected significance threshold is inappropriate. As described above, intermediate phenotypes are polygenic, and their mapping will generate a large number of loci for testing in psychiatric disease. The genetic correlation between disease and intermediate phenotype will be much less than 100%, so that many of the loci cannot both be disease risk locus and a contributor to intermediate phenotype variation; for example, the genetic correlation between cognitive phenotypes and schizophrenia is estimated to be approximately 0.5[17]. Therefore, many loci will have to be tested, and a simple 0.05 significance threshold will be inappropriate. Allowing for ten variants tested (quite probably an underestimate), the sample sizes required for the two effect sizes described above (ORs of 1.10 and 1.08) increase to 12,000 and 37,000 respectively. Once again, the savings in sample size are again not as large as first expected, and given the expense associated with the collection of many intermediate phenotype savings in sample size do not necessarily translate into greater efficiency.
