We examined the roles of a number of additional factors for the lower h2SNP of minimal phenotyping definitions of MDD. First, minimal phenotyping definitions did not simply have a higher environmental contribution to MDD than the stricter definitions. When we assessed h2SNP in MDD cases with high and low exposure to environmental risk factors40, we found that minimal phenotyping definitions of depression (GPpsy and SelfRepDep) showed no significant difference between exposures, which were similar to or lower than those for strictly defined MDD (LifetimeMDD and MDDRecur) (Supplementary Note and Supplementary Table 14). Second, the minimal phenotyping definitions did not merely include milder cases of MDD as previously hypothesized41. Inclusion of milder cases is equivalent to lowering the threshold for disease liability in the population above which ‘cases’ for MDD are defined. Under the liability threshold model42, this did not reduce the h2SNP (Supplementary Note and Extended Data Fig. 1). Instead, we showed through simulations that the lower h2SNP of minimal phenotyping definitions of depression may be due to misdiagnosis of controls as cases of MDD and misclassification of those with other conditions as cases of MDD (Extended Data Figs. 1 and 2).
