The X Factor: Genetics and Female Mental Health

A single X chromosome gene explains a lot about women’s risk of mental illness.

Posted Jun 30, 2015 | Reviewed by Kaja Perina

National Academy of Sciences
Source: National Academy of Sciences

As I pointed out in a previous post, women are at greater risk of many mental illnesses than are men. And as I also quoted authorities on the subject remarking, the stock-in-trade cliché that  this is the result of societal or psychiatric "sexism" simply won’t wash. There are real, fundamental differences in the two sexes’ vulnerability to mental illness that appear to be at the biological level. Indeed, the previous post featured one possibility: the so-called “extreme female brain theory” of psychosis

If being female were a factor in mental illness as it indeed appears to be, a basis might be found in genetic sex differences. Although mammals inherit an equal number of chromosomes from each parent, one of these—the sex chromosome—can be either an X or a Y. Female mammals always have two Xs, but males have an X and a Y.

The evolutionary consequence of this is that, given a normal, equitable sex ratio, there will always be twice as many X genes riding in female as opposed to male bodies. And this in turn means that natural selection will act on female-benefitting X genes twice as often as it will on male-benefitting ones (all other things being equal). Females have a greater vested genetic self-interest in social co-operation among their offspring than do males because they are equally related to all of them. But fathers need not be: Mother’s baby—Father’s? maybe! Thanks to this principle, a father’s genetic self-interest may favour his children’s selfish behaviour—at least if it serves their survival and reproductive success at the expense of siblings to whom he is not related. If mentalism understood as our evolved ability to get on with other people by mental, emotional, and social means is affected by X genes as it is known to be, the clear implication must be that an imbalance in favour of X gene expression might result in hyper-mentalism, which according to the imprinted brain’s diametric model of the mind and of mental illness, is the key factor in psychotic spectrum disorders (PSDs).

As my colleague, Bernard Crespi (writing with Summers and Dorus) has pointed out, triplication of the X chromosome in so-called "super females" is associated with PSD, with XXX subjects having brain imaging similar to that of schizophrenics. Indeed, in Klinefelter’s syndrome (XXY) there is a 4-10 times heightened risk of psychosis, with more positive female-typical symptoms (auditory hallucinations and paranoia) and a female-typical age of onset along with neuro-anatomy similar to that seen in schizophrenia.

To understand how this might work at the genetic level, you need to know about one of the most remarkable genes in the genome: XIST. This is the name of the X chromosome gene located at the X Inactivation Centre (XIC) illustrated at the top which controls X inactivation (or Lyonization as it is also called after Mary Lyon (1925-2014), who discovered it). Because females have two X chromosomes, one is usually largely shut down in each cell to avoid double-dosing of X gene products, bringing about a situation like that in males, who have only one X. XIST is the gene that negotiates this in females with its copy on the other X, and then carries out and maintains the inactivation. But as the illustration at the top suggests, the process is complex, and 10-15% of X genes—so-called escapees—routinely remain active.

Ji, B., et al., EBioMedicine (2015)
XIST and KDM5C over-expression: Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red=patients with various ethnic backgrounds with either bipolar (mixed BP) or recurrent major depression (mixed MDR). 
Source: Ji, B., et al., EBioMedicine (2015)

Now research to appear in EBioMedicine reports that XIST is significantly over-expressed in the cells of female patients with either bipolar disorder or major depression. The X-linked escapee gene KDM5C, whose expression is highly correlated with that of XIST, also displays significant up-regulation in the patients’ cells (above), and studies of human postmortem brains also shows over-expression of XIST in female psychiatric patients. The authors of the new study propose that over-expression of XIST may cause or result from subtle alteration of X chromosome inactivation,

which up-regulates the expression of some X-linked escapee genes including KDM5C. Over-expression of X-linked genes could be a common mechanism for the development of psychiatric disorders between patients with those rare genetic diseases and the general population of female psychiatric patients with XIST over-expression.

And of course, if this is true, it might explain both why women are more prone to particular mental illnesses like depression and why—given that women have two Xs to males’ one—they are more prone to PSD overall. Indeed, as the authors add, “Our studies suggest that XIST and KDM5C expression could be used as a biological marker for diagnosis of psychiatric disorders in a significantly large subset of female patients.” And a whole new world of psychiatric treatment for women that no one could suspect of sexism opens up when they speculate that “Reversing abnormal expression of the X-linked genes in affected females may potentially be a new strategy for future treatment of psychiatric disorders.”

Finally, this remarkable research also suggests that, if up-regulation of X genes is found in PSDs, down-regulation of X genes as a result of unerased inactivation markers on the X a person got from their mother might also be predicted in autism spectrum disorders (ASDs), such as Asperger’s syndrome. In earlier posts, I called this “Lingering Lyonization” and later I pointed out that the idea had been independently anticipated and is indeed now being actively investigated by researchers. If this were to be confirmed, X chromosome gene expression would have been shown to fit the predictions of the imprinted brain theory just as neatly as imprinted gene expression appears to do: up-regulated in PSD but down-regulated in ASD! 

(With thanks to Graham Rook for bringing this to my attention.)