Here we identified a set of genes with frequent expression changes in the postmortem brain of MDD subjectsand show that this gene set is genetically related to brain and organ illnesses frequently associated with MDD. Specifically, we performed a meta-analysis of eight gene array studies in three corticolimbic brain regions and identified ~450 genes frequentlyderegulated in MDD (n=103 subjects, 50.5%MDD). These MetaA-MDD genes includepreviously-implicated neuroplasticity- and stress-related genes (CRH, BDNF, VGF), encompass multiple synaptic and signaling pathways, and suggests complex changes in cell structure and function. MetaA-MDD genes display low connectivity andhubnessin coexpression networks andare evenly distributed throughout the genome. However, MetaA-MDD genesare significantly over-represented in gene sets identified by the genome-wide association studies for brain disorders and organ diseases sharing clinical co-morbidity with MDD (e.g., cardiovascular, metabolic syndrome), but not for other diseases or body functions. Together, this study describes a robustmolecular characterization of altered brain function in MDD, and provides evidence for a shared genetic structure linking MDD andrelated illnesses, together biologically defining abroader dimensional definition ofa depressive-like syndrome.