MDD is suspected to have important phenotypic heterogeneity, and association analyses might yield clearer findings if clinical features are incorporated into genetic analyses. Thus, we conducted predefined secondary analyses intended to index plausible sources of phenotypic heterogeneity in MDD cases. (a) Sex. As the lifetime prevalence of MDD is approximately two times greater in females,54,55 we conducted association analyses separately in males and females to evaluate sex-specific genetic risk variants. (b) Recurrence and age of onset. As recurrence and age of onset may index heterogeneity in MDD,10,56 we analyzed early-onset MDD (≤30 years), recurrent MDD (≥2 episodes), pre-pubertal onset MDD (≤12 years, see Weissman et al.57) and age of onset of MDD as a quantitative trait. (c) Symptoms. As MDD is phenotypically heterogeneous, we obtained MDD symptom data from 88% of all MDD cases (the nine DSM-IV ‘A’ criteria disaggregated to code increase and decrease in appetite, weight, sleep and energy level). Latent class cluster models were fit to binary responses for these MDD ‘A’ criteria, and identified three latent classes in MDD cases characterized by weight loss/insomnia, weight gain/insomnia
