These examples provide a salutary lesson. A researcher might perform a genetic association study of a candidate gene or a GWAS-confirmed variant and obtain a result with a P-value less than 0.05, and therefore conclude that the hypothesized association is proven. However, recall that the genetic architecture of intermediate phenotypes resembles the genetic architecture of other complex traits. If the effect size detected is inconsistent with that expected, then the result should be treated with the same scepticism due any unexpected finding. Extraordinary claims require extraordinary evidence, and not all P-values are created equal [67]. Loci with effect size equivalent to an OR greater than 2, or explaining more than 1% of phenotypic variance, are extremely rare, while those explaining more than 5% of the variance are almost unheard of.
