Results from “-omic” studies of functional features of cells and tissues are necessary to understand the biological implications of results of GWA for complex disorders42. To further elucidate the biological relevance of the major depression findings, we integrated the results with a wide range of functional genomic data. First, using enrichment analyses, we compared the major depression GWA findings to bulk tissue mRNA-seq from GTEx43. Only brain samples showed significant enrichment (Fig. 3A), and the three tissues with the most significant enrichments were all cortical. Prefrontal cortex and anterior cingulate cortex are important for higher-level executive functions and emotional regulation which are often impaired in MDD. Both of these regions were implicated in a large meta-analysis of brain MRI findings in adult MDD cases44. Second, given the predominance of neurons in cortex, we confirmed that the major depression genetic findings connect to genes expressed in neurons but not oligodendrocytes or astrocytes (Fig. 3B)45. Given the different methods used by the seven MDD/major depression cohorts in this study, demonstration of enrichment of association signals in the brain regions expected to be most relevant to MDD provides independent support for the validity of our approach.
