Abnormal X Chromosome Inactivation in Females with Major Psychiatric Disorders

Mania, major depression and schizophrenia are severe brain disorders. No biological hallmark has been identified for any of these disorders. Here, we report that abnormal X chromosome inactivation often presents with a variety of major psychiatric disorders in a significantly large portion of female patients from the general population. X chromosome inactivation is well preserved in human lymphoblastoid cells. Expression of XIST, KDM5C, and other genes on X chromosome is significantly higher in the lymphoblastoid cells of female patients than in those of female healthy controls. We found that XIST and KDM5C expression can be used as a potential diagnostic hallmark for this sub-population of patients. Preliminary studies also suggest an increased XIST expression in postmortem brains from female patients with schizophrenia, bipolar disorder, and major depression. An increased gene dosage from some genes on X chromosome may contribute to development of psychiatric disorders since functional disomy of partial X chromosome have been suggested to cause mental retardation and other developmental abnormalities. Mutation of KDM5C gene was reported to cause X-linked syndromic mental retardation. We propose that abnormal X chromosome inactivation could play a causal role in development of major psychiatric disorders in females. Correction of abnormal X chromosome inactivation may prevent and/or cure major psychiatric disorders in female patients in future.