Major Depressive Disorder (MDD) is highly prevalent(1) and one of the main contributors to disability worldwide(2). Though the heritability of MDD has been estimated to be 37%(3), the search for specific genetic variants has not yet been successful: the largest GWAS mega-analysis to date detected no significant associations with common polymorphisms(4). Statistical hints suggest that depression liability is polygenic, with the majority of variance due to joint effects of multiple loci with small effects scattered across the genome(5;6). Failure to detect single effects is attributable to underpowered sample sizes and to depression’s clinical heterogeneity, that additionally compromises the power of association studies(5–9). Patients with the same diagnosis of MDD (any five out of nine DSM-5 accessory symptoms(10)) may endorse very different symptom profiles. From clinical observations, criteria to identify two severe subtypes – each present in ~25–35% of patients - based on more homogenous symptom profiles have been proposed: typical/melancholic and atypical(11), reflected in the DSM-5 specifiers for melancholic and atypical depression. However, not all DSM criteria have been justified by research, and recent studies based on data-driven techniques highlighted
