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Over-expression of XIST, the Master Gene for X Chromosome Inactivation, in Females With Major Affective Disorders.

Ji B, Higa KK, Kelsoe JR, Zhou X - EBioMedicine (2015)

Bottom Line: 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).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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

ABSTRACT

Background: 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.

Methods: 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.

Findings: 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.

Interpretations: 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.

Research in context: 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.

No MeSH data available.


Related in: MedlinePlus

Over-expression of XIST in postmortem brains of female patients with major psychiatric disorders. All 48 female RNA samples from postmortem human brains were kindly provided by Stanley Medical Research Institute. Expression of XIST and KDM5C was double-blindly quantified. Each dot represents a human subject. Gray = all subjects; black = healthy female controls (CTRL); red = female patients with bipolar disorder (BP), recurrent major depression (MDR), and schizophrenia (SCZ). (A) To assess cell heterogeneity of the samples, GFAP expression was quantified to evaluate relative abundance of glial cells in the samples. 2 samples displayed high levels of GFAP expression above 3 interquartile ranges (IQR) above the upper quartile using boxplot analysis. Therefore, both were determined as extreme outliers and excluded for further analyses. (B) There was one control sample with a very high level of XIST expression that is qualified as an outlier. Due to small sample size, it was retained. There was significantly higher XIST expression in bipolar disorder (t(24) = − 2.07, p = 0.025), and a trend of high XIST in major depression (t(20) = − 1.35, p = 0.096). Significantly higher XIST expression was also detected when bipolar disorder and major depression were combined or when all patients were combined. (C) There was no significant difference in KDM5C expression between the control group and any patient group. (D) There was no correlation between XIST and KDM5C expression in the postmortem brains of the patients.
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f0030: Over-expression of XIST in postmortem brains of female patients with major psychiatric disorders. All 48 female RNA samples from postmortem human brains were kindly provided by Stanley Medical Research Institute. Expression of XIST and KDM5C was double-blindly quantified. Each dot represents a human subject. Gray = all subjects; black = healthy female controls (CTRL); red = female patients with bipolar disorder (BP), recurrent major depression (MDR), and schizophrenia (SCZ). (A) To assess cell heterogeneity of the samples, GFAP expression was quantified to evaluate relative abundance of glial cells in the samples. 2 samples displayed high levels of GFAP expression above 3 interquartile ranges (IQR) above the upper quartile using boxplot analysis. Therefore, both were determined as extreme outliers and excluded for further analyses. (B) There was one control sample with a very high level of XIST expression that is qualified as an outlier. Due to small sample size, it was retained. There was significantly higher XIST expression in bipolar disorder (t(24) = − 2.07, p = 0.025), and a trend of high XIST in major depression (t(20) = − 1.35, p = 0.096). Significantly higher XIST expression was also detected when bipolar disorder and major depression were combined or when all patients were combined. (C) There was no significant difference in KDM5C expression between the control group and any patient group. (D) There was no correlation between XIST and KDM5C expression in the postmortem brains of the patients.

Mentions: With a limited number of available postmortem human brains from female patients with major psychiatric disorders, we double-blindly examined expression of XIST and KDM5C genes in the RNA of cingulate cortex from both Array Collection and Depression Collection from Stanley Medical Research Institute (SMRI). One of many confounding factors in gene expression analysis is the potential cell heterogeneity of the brain samples. If some brain tissues have significantly more glial cells, they may particularly distort quantification of relative XIST expression, presumably because XIST expression is more dependent on the number of individual cells than the β-actin reference control. Therefore, we first conducted analysis of GFAP mRNA expression to evaluate relative abundance of glial cells in all 48 female samples received from SMRI. Two brain samples exhibited very high levels of GFAP mRNA expression that was over 3 standard deviations above the group mean (Fig. 6A). Both samples were determined as extreme outliers because they lie outside of 3 interquartile ranges (IQR) above the upper quartile using boxplot analysis. They were therefore excluded for further analysis. Both XIST and KDM5C expression were quantified in the cingulate cortex. One control sample displayed a very high level of XIST expression. It is difficult to know whether it is caused by other confounding factors that associate with human postmortem brain tissues. Nevertheless, we still detected a significantly higher level of XIST expression in the bipolar group (p < 0.05) and a trend of high level of XIST expression in the major depression group (p < 0.1) (Fig. 6B). Significantly higher XIST expression was also detected when bipolar disorder and major depression are combined (p < 0.05) or when all patients are combined (p < 0.05). No significant difference was observed in KDM5C expression in the cingulate cortex between the control group and each of the patient groups (Fig. 6C). Neither a correlation was found between XIST and KDM5C expression in the cingulate cortex of postmortem human brains (Fig. 6D). In summary, the postmortem brain data supported that over-expression of XIST occurs in both lymphoblastoid cells and the postmortem brains of female patients with bipolar disorder or major depression.


Over-expression of XIST, the Master Gene for X Chromosome Inactivation, in Females With Major Affective Disorders.

Ji B, Higa KK, Kelsoe JR, Zhou X - EBioMedicine (2015)

Over-expression of XIST in postmortem brains of female patients with major psychiatric disorders. All 48 female RNA samples from postmortem human brains were kindly provided by Stanley Medical Research Institute. Expression of XIST and KDM5C was double-blindly quantified. Each dot represents a human subject. Gray = all subjects; black = healthy female controls (CTRL); red = female patients with bipolar disorder (BP), recurrent major depression (MDR), and schizophrenia (SCZ). (A) To assess cell heterogeneity of the samples, GFAP expression was quantified to evaluate relative abundance of glial cells in the samples. 2 samples displayed high levels of GFAP expression above 3 interquartile ranges (IQR) above the upper quartile using boxplot analysis. Therefore, both were determined as extreme outliers and excluded for further analyses. (B) There was one control sample with a very high level of XIST expression that is qualified as an outlier. Due to small sample size, it was retained. There was significantly higher XIST expression in bipolar disorder (t(24) = − 2.07, p = 0.025), and a trend of high XIST in major depression (t(20) = − 1.35, p = 0.096). Significantly higher XIST expression was also detected when bipolar disorder and major depression were combined or when all patients were combined. (C) There was no significant difference in KDM5C expression between the control group and any patient group. (D) There was no correlation between XIST and KDM5C expression in the postmortem brains of the patients.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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f0030: Over-expression of XIST in postmortem brains of female patients with major psychiatric disorders. All 48 female RNA samples from postmortem human brains were kindly provided by Stanley Medical Research Institute. Expression of XIST and KDM5C was double-blindly quantified. Each dot represents a human subject. Gray = all subjects; black = healthy female controls (CTRL); red = female patients with bipolar disorder (BP), recurrent major depression (MDR), and schizophrenia (SCZ). (A) To assess cell heterogeneity of the samples, GFAP expression was quantified to evaluate relative abundance of glial cells in the samples. 2 samples displayed high levels of GFAP expression above 3 interquartile ranges (IQR) above the upper quartile using boxplot analysis. Therefore, both were determined as extreme outliers and excluded for further analyses. (B) There was one control sample with a very high level of XIST expression that is qualified as an outlier. Due to small sample size, it was retained. There was significantly higher XIST expression in bipolar disorder (t(24) = − 2.07, p = 0.025), and a trend of high XIST in major depression (t(20) = − 1.35, p = 0.096). Significantly higher XIST expression was also detected when bipolar disorder and major depression were combined or when all patients were combined. (C) There was no significant difference in KDM5C expression between the control group and any patient group. (D) There was no correlation between XIST and KDM5C expression in the postmortem brains of the patients.
Mentions: With a limited number of available postmortem human brains from female patients with major psychiatric disorders, we double-blindly examined expression of XIST and KDM5C genes in the RNA of cingulate cortex from both Array Collection and Depression Collection from Stanley Medical Research Institute (SMRI). One of many confounding factors in gene expression analysis is the potential cell heterogeneity of the brain samples. If some brain tissues have significantly more glial cells, they may particularly distort quantification of relative XIST expression, presumably because XIST expression is more dependent on the number of individual cells than the β-actin reference control. Therefore, we first conducted analysis of GFAP mRNA expression to evaluate relative abundance of glial cells in all 48 female samples received from SMRI. Two brain samples exhibited very high levels of GFAP mRNA expression that was over 3 standard deviations above the group mean (Fig. 6A). Both samples were determined as extreme outliers because they lie outside of 3 interquartile ranges (IQR) above the upper quartile using boxplot analysis. They were therefore excluded for further analysis. Both XIST and KDM5C expression were quantified in the cingulate cortex. One control sample displayed a very high level of XIST expression. It is difficult to know whether it is caused by other confounding factors that associate with human postmortem brain tissues. Nevertheless, we still detected a significantly higher level of XIST expression in the bipolar group (p < 0.05) and a trend of high level of XIST expression in the major depression group (p < 0.1) (Fig. 6B). Significantly higher XIST expression was also detected when bipolar disorder and major depression are combined (p < 0.05) or when all patients are combined (p < 0.05). No significant difference was observed in KDM5C expression in the cingulate cortex between the control group and each of the patient groups (Fig. 6C). Neither a correlation was found between XIST and KDM5C expression in the cingulate cortex of postmortem human brains (Fig. 6D). In summary, the postmortem brain data supported that over-expression of XIST occurs in both lymphoblastoid cells and the postmortem brains of female patients with bipolar disorder or major depression.

Bottom Line: 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).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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

ABSTRACT

Background: 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.

Methods: 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.

Findings: 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.

Interpretations: 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.

Research in context: 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.

No MeSH data available.


Related in: MedlinePlus