In summary, our results suggest that MDD subtypes based on symptom profiles are characterized by partially distinct polygenic liabilities and may represent more homogeneous phenotypes. Similarly to other complex diseases MDD may represent a diagnostic aggregation of biologically different subtypes. As shown by recent simulations studies(7;8), this heterogeneity could severely compromise the power of association studies. Moreover, the finding of partially distinct genetic signature across more homogenous subtypes suggest translational implication in the long term: it could be hypothesized that distinct subtypes may specifically respond to different treatments. Our results provide proof of principle evidence that should stimulate further studies scaling up the dissection of MDD heterogeneity in larger samples. As we demonstrated, the use of cost-effective sub-phenotyping strategies to identify subtypes, in particular atypical, may be a successful strategy to harmonize phenotypes across different cohorts. While we dissected MDD along symptom-profiles, other clinical features (e.g.; age of onset, post-partum onset, sensitivity to environmental stressors) may be also tested in future studies. Disentangling MDD heterogeneity (provided a constant parallel effort in increasing samples size of genetic studies) may help the psychiatric field moving forward in the search for molecular roots of depression.
