Genetics of depression show sexual dimorphism?

The genetics of depression has been an interestly difficult problem. In this paper, which is long, complex, and well worth reading, post mortem brain samples are used to demonstrate differential genetic expression by region between people with depression and controls, that differ by sex. This is then replicated in mice experimental models, and using a known genetic dataset.

Thie review paper is long and complex but it can be summed up in the diagram below.

Previous attempts to decipher the genetic bases of MDD met with limited success, although more recent studies have proven more successful. Notably, several gene targets identified in these studies are found within the top gene networks in our study and highlight the heterogeneity of the disorder, not only from a clinical but also from a molecular and mechanistic point of view. While these studies reported no MDD-associated genetic sex difference41, we found these gene targets within highly sexually dimorphic gene networks, suggesting that the sexual dimorphism defining MDD may be taking place at the transcriptional rather than at the genetic levels. More work is required to understand this complex relationship, as well as the basis of the sexual dimorphism observed in human MDD, part of which may rely on gonadal hormones and chromosomally based sex differences.

To conclude, by defining the transcriptional signatures of males and females with MDD, we provided solid evidence uncovering the molecular and cellular mechanisms underlying sex-specific stress susceptibility. This study represents a robust resource for the study of sex differences in mood disorders and the identification of molecular pathways which may be significantly involved in mediating the effect of stress in males and females. Future investigations should extend this work to assess the potential associations between brain and blood gene networks, with the promise that the latter might reveal gene signatures related to diagnostic subtypes or treatment responses. Nevertheless, by showing here that MDD in males and females originates from the alterations of mostly distinct genes converging on partly similar functional pathways, we provide a strong basis on which to build the foundation for a better understanding of the molecular mechanisms taking place in the brain of males and females with MDD, insights which can be used to develop treatment strategies targeted selectively to the two sexes.

Nature Medicine (2017) doi:10.1038/nm.4386

The next questions relate to how these differential gene expressions interact with the expression of such genes in blood, how this will influence treatment of what is clearly not merely one psychopathological process, and how does this interact with the known increase in depression among women of childbearing years.

I await the horror of the woman’s study department with interest.