X chromosome plays an important

X chromosome plays an important role in the development of psychiatric disorders (Goldstein et al., 2013; Perrin et al., 2010; Crow, 2013; Ross et al., 2001, 2006). Over-dosage of X-linked escapee genes due to an extra X chromosome was suggested to contribute to the development of psychiatric symptoms in both Klinefelter syndrome (XXY) and Triple X syndrome (XXX) (DeLisi et al., 2005). In lymphoblastoid cells from the female psychiatric patients, not all studied X-linked escapee genes displayed concomitant up-regulation with XIST over-expression. For example, escapee gene RPS4X has normal expression in the patients\' lymphoblastoid cell lines. Investigation of more X-linked escapee genes is needed in the future. Nevertheless, it is plausible that over-expression of XIST and some escapee genes may be a common mechanism underlying development of psychiatric disorders between the rare patients with aneuploid X chromosomes and a subset of the general population of female psychiatric patients with a normal karyotype. Among these escapee genes, KDM5C is particularly interesting since its haploinsufficiency causes mental retardation (Ounap et al., 2012; Fieremans et al., 2015) or mood disorder (Jensen et al., 2005) in females. Mutations of KDM5C generate much more severe mental retardation in males (Jensen et al., 2005; Rujirabanjerd et al., 2010). It will be interesting to know whether KDM5C over-expression may contribute to psychiatric symptoms in the female patients. Our studies suggest that subtle alteration of XCI could be a unique genetic risk factor for psychiatric disorders in women. It could be argued that the risk factor is XIST over-expression rather than subtle alteration of XCI. This alternative hypothesis, however, cannot readily explain the high correlation between expression of XIST and the X-linked escapee gene KDM5C in the patients. Why does over-expression of XIST and KDM5C occur in both bipolar disorder and major depression? One explanation is that psychiatric disorders are not distinct individual diseases, but a spectrum of mental disorders. For example, some patients display both mania and depression. Another explanation is that there are other modifier genes on order eicosapentaenoic acid that interact with environment to result in different clinical symptoms. In fact, patients with either Klinefelter syndrome or Triple X syndrome display a variety of psychiatric symptoms that can be classified as bipolar disorder, major depression, schizophrenia, and other psychiatric disorders (DeLisi et al., 1994, 2005; Tartaglia et al., 2012). A thorough analysis to compare expression of X-linked genes between the patients with Triple X syndrome and female psychiatric patients with a normal karyotype will help understand the role of over-dosage of X-linked genes in the pathogenesis of psychiatric disorders. Reversing abnormal expression of the X-linked genes in affected females may potentially be a new strategy for future treatment of psychiatric disorders. The following are the supplementary data related to half-life article.
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Introduction Bipolar disorder (BP) is a major psychiatric disorder that is disabling and recurrent. It is highly heritable (more than 70%) (Tsuang and Faraone, 2000) and is characterized by hypo/manic episodes. Pioneering work on the trajectory of BP has identified early-risk syndromes that precede the official onset (Akiskal et al., 1985; Duffy et al., 2014; Mesman et al., 2013) and are proposed to represent early stages in the development of BP (Duffy et al., 2014). Identifying the early stages of BP is important for prevention and early intervention strategies, which have been shown to be successful in early psychosis and can avert or delay the transition from clinically ultra-high-risk conditions to a full psychotic disorder (McGorry et al., 2009). The early symptoms (and syndromes) that precede full-blown BP are usually non-specific during childhood (e.g., anxiety, sleep disturbance, and attention deficit hyperactivity disorder (ADHD) symptoms/signs) and then manifest as adjustment disorder during early adolescence and later as subthreshold depression and/or hypomania that falls short of the official criteria (Akiskal et al., 1985; Correll et al., 2014; Duffy et al., 2014; Egeland et al., 2000; Mesman et al., 2013). In a Canadian follow-up study (up to 16years) of the offspring of parents with BP, the accumulated incidence of major mood disorders (depressive spectrum and bipolar disorders) was unfortunately high — 83.3% (Duffy et al., 2014). Another Dutch study of genetically high-risk offspring (12years of follow-up) showed that 72% of the offspring developed a lifetime DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) axis I disorder (Mesman et al., 2013). Furthermore, in modeling the developmental stages of BP – from non-specific symptoms, followed by minor mood disorder, major depressive episodes, and finally hypo/manic episodes – once entering the model, these high-risk offspring progressed linearly through the stages without skipping any stage (Duffy et al., 2014), which suggests a progressive process and an urgent need for intervention. Recently, clinical staging models for BP that cut across the dichotomous category of the present classification systems have been proposed with attempts at better understanding the underlying pathophysiology and providing potential targets for early intervention (Frank et al., 2014; Scott et al., 2013). The clinical staging models hypothesize that there are stages (0, 1a and 1b) that precede full-blown BP. Stage 0 and stage 1a may together represent a phase of biological vulnerability (i.e., genetic risk) with no or mild, non-specific symptoms that can be subsumed into the HR stage (Scott et al., 2013), whereas stage 1b can be described as ultra-high-risk (UHR), manifesting subthreshold syndromes, alterations in cortical (and subcortical) volumes, and deficits in cognitive function (Frank et al., 2014).