Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
EBioMedicine. 2015 Jun 14;2(8):909-18. doi: 10.1016/j.ebiom.2015.06.012. eCollection 2015 Aug.
Psychiatric disorders are common mental disorders without a pathological biomarker. Classic genetic studies found that an extra X chromosome frequently causes psychiatric symptoms in patients with either Klinefelter syndrome (XXY) or Triple X syndrome (XXX). Over-dosage of some X-linked escapee genes was suggested to cause psychiatric disorders. However, relevance of these rare genetic diseases to the pathogenesis of psychiatric disorders in the general population of psychiatric patients is unknown.
XIST and several X-linked genes were studied in 36 lymphoblastoid cell lines from healthy females and 60 lymphoblastoid cell lines from female patients with either bipolar disorder or recurrent major depression. XIST and KDM5C expression was also quantified in 48 RNA samples from postmortem human brains of healthy female controls and female psychiatric patients.
We found that the XIST gene, a master in control of X chromosome inactivation (XCI), is significantly over-expressed (p = 1 × 10(- 7), corrected after multiple comparisons) in the lymphoblastoid cells of female patients with either bipolar disorder or major depression. The X-linked escapee gene KDM5C also displays significant up-regulation (p = 5.3 × 10(- 7), corrected after multiple comparisons) in the patients' cells. Expression of XIST and KDM5C is highly correlated (Pearson's coefficient, r = 0.78, p = 1.3 × 10(- 13)). Studies on human postmortem brains supported over-expression of the XIST gene in female psychiatric patients.
We propose that over-expression of XIST may cause or result from subtle alteration of XCI, 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. 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.
Due to lack of biological markers, diagnosis and treatment of psychiatric disorders are subjective. There is utmost urgency to identify biomarkers for clinics, research, and drug development. We found that XIST and KDM5C gene expression may be used as a biological marker for diagnosis of major affective disorders in a significantly large subset of female patients from the general population. Our studies show that over-expression of XIST and some X-linked escapee genes may be a common mechanism for development of psychiatric disorders between the patients with rare genetic diseases (XXY or XXX) and the general population of female psychiatric patients.
精神障碍是一种常见的精神疾病，没有病理性生物标志物。经典的遗传学研究发现，多余的 X 染色体常导致 Klinefelter 综合征（XXY）或 Triple X 综合征（XXX）患者出现精神症状。有人推测，一些 X 连锁逃逸基因的过表达会导致精神障碍。然而，这些罕见的遗传疾病与精神病患者人群中精神障碍的发病机制的相关性尚不清楚。
研究了 36 株来自健康女性的淋巴母细胞系和 60 株来自双相情感障碍或复发性重度抑郁女性患者的淋巴母细胞系中的 XIST 和几个 X 连锁基因。还定量检测了 48 例来自健康女性对照和女性精神科患者死后人脑的 RNA 样本中的 XIST 和 KDM5C 表达。
我们发现，X 染色体失活（XCI）的主要调控基因 XIST 在双相情感障碍或重度抑郁女性患者的淋巴母细胞中表达显著升高（p=1×10(-7)，经多重比较校正）。X 连锁逃逸基因 KDM5C 在患者细胞中也显示出显著的上调（p=5.3×10(-7)，经多重比较校正）。XIST 和 KDM5C 的表达高度相关（皮尔逊系数 r=0.78，p=1.3×10(-13)）。对人类死后大脑的研究支持了女性精神科患者 XIST 基因的过度表达。
我们提出，XIST 的过表达可能导致或源于 XCI 的细微改变，从而上调包括 KDM5C 在内的一些 X 连锁逃逸基因的表达。X 连锁基因的过表达可能是那些罕见遗传疾病患者和 XIST 过表达的女性精神科患者总体人群中精神障碍发生的共同机制。我们的研究表明，XIST 和 KDM5C 的表达可以作为精神障碍诊断的生物学标记，用于女性患者的一个显著亚组。
由于缺乏生物学标志物，精神障碍的诊断和治疗具有主观性。非常需要确定用于临床、研究和药物开发的生物标志物。我们发现，XIST 和 KDM5C 基因表达可作为一个显著的女性患者亚组人群中诊断主要情感障碍的生物学标记，这些女性患者来自普通人群。我们的研究表明，XIST 和一些 X 连锁逃逸基因的过表达可能是罕见遗传疾病（XXY 或 XXX）患者和女性精神科患者总体人群中精神障碍发生的共同机制。
