Overexpression of two genes involved in X chromosome inactivation might serve as biomarkers for major affective disorders in women, new research suggests.
In fact, it is possible that overexpression of the X-inactive specific transcript (XIST) gene and the X-linked “escapee” gene KDM5C “may potentially be used as a prodromal biomarker, since X chromosome inactivation [XCI] occurs during embryogenesis,” study investigator Xianjin Zhou, PhD, Department of Psychiatry, University of California, San Diego, told Medscape Medical News.
The study was published online June 16 in EBioMedicine.
Toward a Cure
The investigators examined XIST and several X-linked genes in 36 lymphoblastoid cell lines from healthy women and 60 lymphoblastoid cell lines from women with bipolar disorder or recurrent major depression. They also quantified expression of XIST and KDM5C in 48 RNA samples from postmortem brain tissue from women who had been diagnosed with psychiatric disorders and from women who had had no psychiatric illness.
They observed significant overexpression of XIST and KDM5C in lymphoblastoid cells from women with bipolar disorder or major depression. There was a high degree of correlation between expression of XIST and KDM5C.
The human postmortem brain studies “supported overexpression of the XIST gene in women with psychiatric disorders,” they report.
The XIST gene inactivates one of the two copies of the X chromosome. The presence of an extra X chromosome causes Klinefelter syndrome (XXY) and triple X syndrome (XXX). And although both syndromes are rare in the general population (about 0.1%), there is a four- to fivefold increase in prevalence of XXY and XXX in psychiatric inpatients. Overexpression of XIST has been seen in women with bipolar disorder, major depressive disorder, and schizophrenia.
“We propose that overexpression of XIST may cause or result from subtle alteration of XCI, which up-regulates the expression of some X-linked escapee genes including KDM5C. Overexpression 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 overexpression,” the authors note.
“Reversing abnormal function of the inactive X chromosome may therefore be a potentially new strategy to cure the diseases,” said Dr Zhou.
The researchers also note that it may be feasible to measure XIST and KDM5C expression in girls at childhood or during early adolescence to gauge their risk of developing major psychiatric disorders in young adulthood.
“However, psychiatric disorders are genetically heterogeneous, not all women patients will have abnormal activity of the inactive X chromosome,” Dr Zhou cautioned.
“We have to realize,” he added, “that our studies were conducted in a small number of patients (60 female patients). We have to expand our studies to include several hundreds of patients with a variety of psychiatric disorders to estimate the prevalence and the risk ratio of abnormal activity of XCI in the general population of female patients. We are submitting our research proposals to continue the studies.”
“Psychosis genetics has ploughed an unyielding furrow,” Timothy J. Crow, PhD, of the University Department of Psychiatry, Warneford Hospital, Oxford, United Kingdom, notes in a commentary published with the study.
“The time for predictions that with sufficient markers the three prototypical conditions (schizophrenia, bipolar or manic-depressive disorder and unipolar depression) will each be found associated with specific chromosomal loci is long past,” Dr Crow notes.
This new study “draws attention to XIST as the initiator of the inactivation process and to the KDM5C gene, as normally escaping its influence,” he points out.
“Two other members of this select class of 36 XY homologous nonrecombining gene pairs are already held to be relevant to psychiatric disorders. The NLGN4 gene has been associated with autism, and the Protocadherin11XY gene-pair that lies within the Xq21.3/Yp11.2 region of homology created by a duplication from Xq to Yp at 6MYA 10 is proposed as a candidate in relation to psychosis. It may be that others of the genes in the XY nonrecombining regions of homology are relevant. If so [this new study] will prove to have opened up a new field of investigation in psychosis genetics,” Dr Crow concludes.
The authors report no relevant financial relationships.
EBioMedicine. Published online June 16, 2015