Discussion
We report almost no overlap in transcriptional changes across corticolimbic brain regions in men and women with MDD, but instead opposite transcriptional changes. Our results suggest that men with MDD have decreases, but women with MDD have increases in synapse-related genes. Immune-related reductions characterized female MDD. Cell type-specific analysis suggests increases in oligodendrocyte- and microglia-specific genes in men with MDD, but decreases in markers of these cell types in women with MDD. Together, these findings point towards distinct, and even opposite molecular changes in MDD in men and women.
Our results are partially consistent with results from a recent publication reporting sex-specific changes in MDD (46). While we also found very little overlap in DE genes in men and women with MDD, our results indicate a high level of transcriptional overlap in genes changed in opposite directions. In fact, we used our statistical methods on the data generated by Labonte et al. (46) and found very similar, but unreported opposite transcriptional results. Brains used in the previous publication were from a different brain bank, supporting the generalizability of our findings. Here, we include results from the AMY, which is not included in Labonte et al. (46). Although consistent with our hypothesis, it is somewhat surprising that these sex-specific molecular changes in MDD were not reported previously. One reason might be because many previous postmortem brain analyses in MDD were performed in mostly (or only) men. Studies that included both sexes mostly did not have sufficient statistical power to stratify by sex, although a few prior reports have hinted at sex differences in MDD (see examples in the Introduction) We believe that our meta-analysis/regression approach gave us the statistical power to investigate larger-scale profiles of molecular changes occurring in the brains of men and women with MDD.
