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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, KDM5C, and KDM6A in patients with recurrent major depression. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female patients with recurrent major depression (MDR); gray = healthy female controls with various ethnic genetic backgrounds (mixed CTRL). Multiple comparisons of Student's t-tests were corrected with FDR. (A) A significantly larger variation was observed in XIST expression in the patients group (p = 0.001, F-test). There was also a significantly higher level of XIST expression (t(11) = − 4.16, p < 0.01, unequal variances) in the patients than in the controls. (B) Down-regulation of TSIX expression was not statistically significant (t(21) = 1.35, ns). Larger variation was observed in either KDM5C (p = 0.027, F-test) or KDM6A (p = 5.9 × 10− 5, F-test) gene expression in the patients. There was also significantly higher expression of KDM5C (C)(t(13) = − 4.45, p < 0.001, unequal variances) and KDM6A (D)(t(10) = − 2.23, p = 0.05, unequal variances) in the patients lymphoblastoid cells. There is no difference in XIST (E) or KDM5C (F) expression between healthy European Caucasian female controls and healthy female controls with various ethnic genetic backgrounds. (**p < 0.01, *p < 0.05).
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f0010: Over-expression of XIST, KDM5C, and KDM6A in patients with recurrent major depression. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female patients with recurrent major depression (MDR); gray = healthy female controls with various ethnic genetic backgrounds (mixed CTRL). Multiple comparisons of Student's t-tests were corrected with FDR. (A) A significantly larger variation was observed in XIST expression in the patients group (p = 0.001, F-test). There was also a significantly higher level of XIST expression (t(11) = − 4.16, p < 0.01, unequal variances) in the patients than in the controls. (B) Down-regulation of TSIX expression was not statistically significant (t(21) = 1.35, ns). Larger variation was observed in either KDM5C (p = 0.027, F-test) or KDM6A (p = 5.9 × 10− 5, F-test) gene expression in the patients. There was also significantly higher expression of KDM5C (C)(t(13) = − 4.45, p < 0.001, unequal variances) and KDM6A (D)(t(10) = − 2.23, p = 0.05, unequal variances) in the patients lymphoblastoid cells. There is no difference in XIST (E) or KDM5C (F) expression between healthy European Caucasian female controls and healthy female controls with various ethnic genetic backgrounds. (**p < 0.01, *p < 0.05).

Mentions: To investigate whether abnormal expression of XIST and other X-linked genes also presents in females with a different psychiatric disorder, we examined the expression of XIST, TSIX, KDM5C, KDM6A, PGK1, and G6PD genes in the lymphoblastoid cells of female patients with recurrent major depression. These genes were chosen because they displayed significant or trend increases of expression in the female bipolar patients with mania and psychosis. Expression of XIST was significantly higher (p < 0.01) in the female patients with recurrent major depression than in the female healthy controls (Fig. 2A). Down-regulation of TSIX expression was, however, not statistically significant in the female patients with recurrent major depression (Fig. 2B). Expression of KDM5C was also significantly higher (p < 0.001) in the patients with recurrent major depression (Fig. 2C). Consistent with a trend of high KDM6A expression in the female bipolar patients, we observed a significantly higher expression of KDM6A (p < 0.05) in the lymphoblastoid cells of female patients with recurrent major depression (Fig. 2D). No difference was found in either PGK1 or G6PD expression between the female patients and the healthy female controls (Fig. S6A and B). To enlarge the sample size of the healthy female controls, we analyzed expression of XIST, KDM5C and KDM6A genes in a group of healthy females who have various ethnic genetic backgrounds (“mixed”). No difference was observed in either XIST or KDM5C expression between the European Caucasian female controls and the female controls with various ethnic genetic backgrounds (Fig. 2E and F). A slightly higher level of KDM6A expression was observed in the controls with various ethnic backgrounds (Fig. S6C). Given that KDM6A expression varies between different cell cultures of the control samples (Fig. 1F vs Fig. 2D), it is not surprising that its expression was also affected by different ethnic backgrounds. We concluded that ethnic background has little effect on XIST and KDM5C expression. To enlarge the sample sizes of the psychiatric patients, we included more patients who have either bipolar disorder (mania and psychosis) or recurrent major depression with various ethnic backgrounds. Significant difference in either XIST or KDM5C expression was observed between the control group and each of the two patient groups (Fig. 3A and B). Since the same healthy European female Caucasians were used as a calibrator and control for analyses of all other control and patient groups, gene expression in each subject was therefore normalized against the group mean of the healthy European female Caucasians whose cells were co-cultured for quantification. There was a significantly larger variation of XIST expression between the combined control and the combined groups of either bipolar disorder (p = 8 × 10− 5, F-test) or major depression (p = 1 × 10− 10, F-test) (Fig. 3C). When both bipolar and major depression were combined (BP + MDR), a significantly larger variation was observed (p = 1 × 10− 8, F-test). Additionally, significant increase of XIST expression was also detected in bipolar (p = 1 × 10− 7), major depression (p = 0.004), and the combined (BP + MDR) group (p = 1 × 10− 7). Similarly, a larger variation of KDM5C expression was found in bipolar (p = 0.002, F-test), major depression (p = 0.004, F-test), and the combined (BP + MDR) group (p = 0.001, F-test) (Fig. 3D). Significant increase of KDM5C expression was also observed in bipolar disorder (p = 5.4 × 10− 6), major depression (p = 0.001), and the combined (BP + MDR) group (p = 5.3 × 10− 7). A high correlation was observed between XIST and KDM5C expression in all patients' cells (Pearson's coefficient, r = 0.78, p = 1.3 × 10− 13) (Fig. 4A). We explored whether a combination of XIST and KDM5C expression can be used as a potential diagnostic marker to separate the patients from the controls. According to calculation of reference range in clinical blood tests (William et al., 2008), we calculated the reference ranges of XIST and KDM5C expression in the control females to define a “normal” distribution. The upper limit of the reference range is defined as 2 standard deviations above the mean (dashed line, Fig. 4B). Out of 60 patients, 36 have XIST and/or KDM5C expression above their reference ranges. Among them, 20 patients have both XIST and KDM5C expressions above their reference ranges. None of the 36 controls display abnormally high XIST and/or KDM5C expression. Since it would be rare to have a control sample expressing both XIST and KDM5C above their reference ranges, we propose that a combination of both XIST and KDM5C gene expressions may serve as a reliable biological marker for diagnosis of bipolar disorder or major depression in a significantly large subset of female patients.


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, KDM5C, and KDM6A in patients with recurrent major depression. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female patients with recurrent major depression (MDR); gray = healthy female controls with various ethnic genetic backgrounds (mixed CTRL). Multiple comparisons of Student's t-tests were corrected with FDR. (A) A significantly larger variation was observed in XIST expression in the patients group (p = 0.001, F-test). There was also a significantly higher level of XIST expression (t(11) = − 4.16, p < 0.01, unequal variances) in the patients than in the controls. (B) Down-regulation of TSIX expression was not statistically significant (t(21) = 1.35, ns). Larger variation was observed in either KDM5C (p = 0.027, F-test) or KDM6A (p = 5.9 × 10− 5, F-test) gene expression in the patients. There was also significantly higher expression of KDM5C (C)(t(13) = − 4.45, p < 0.001, unequal variances) and KDM6A (D)(t(10) = − 2.23, p = 0.05, unequal variances) in the patients lymphoblastoid cells. There is no difference in XIST (E) or KDM5C (F) expression between healthy European Caucasian female controls and healthy female controls with various ethnic genetic backgrounds. (**p < 0.01, *p < 0.05).
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f0010: Over-expression of XIST, KDM5C, and KDM6A in patients with recurrent major depression. Each dot represents a human subject. Black = healthy European Caucasian female controls (CTRL); red = European Caucasian female patients with recurrent major depression (MDR); gray = healthy female controls with various ethnic genetic backgrounds (mixed CTRL). Multiple comparisons of Student's t-tests were corrected with FDR. (A) A significantly larger variation was observed in XIST expression in the patients group (p = 0.001, F-test). There was also a significantly higher level of XIST expression (t(11) = − 4.16, p < 0.01, unequal variances) in the patients than in the controls. (B) Down-regulation of TSIX expression was not statistically significant (t(21) = 1.35, ns). Larger variation was observed in either KDM5C (p = 0.027, F-test) or KDM6A (p = 5.9 × 10− 5, F-test) gene expression in the patients. There was also significantly higher expression of KDM5C (C)(t(13) = − 4.45, p < 0.001, unequal variances) and KDM6A (D)(t(10) = − 2.23, p = 0.05, unequal variances) in the patients lymphoblastoid cells. There is no difference in XIST (E) or KDM5C (F) expression between healthy European Caucasian female controls and healthy female controls with various ethnic genetic backgrounds. (**p < 0.01, *p < 0.05).
Mentions: To investigate whether abnormal expression of XIST and other X-linked genes also presents in females with a different psychiatric disorder, we examined the expression of XIST, TSIX, KDM5C, KDM6A, PGK1, and G6PD genes in the lymphoblastoid cells of female patients with recurrent major depression. These genes were chosen because they displayed significant or trend increases of expression in the female bipolar patients with mania and psychosis. Expression of XIST was significantly higher (p < 0.01) in the female patients with recurrent major depression than in the female healthy controls (Fig. 2A). Down-regulation of TSIX expression was, however, not statistically significant in the female patients with recurrent major depression (Fig. 2B). Expression of KDM5C was also significantly higher (p < 0.001) in the patients with recurrent major depression (Fig. 2C). Consistent with a trend of high KDM6A expression in the female bipolar patients, we observed a significantly higher expression of KDM6A (p < 0.05) in the lymphoblastoid cells of female patients with recurrent major depression (Fig. 2D). No difference was found in either PGK1 or G6PD expression between the female patients and the healthy female controls (Fig. S6A and B). To enlarge the sample size of the healthy female controls, we analyzed expression of XIST, KDM5C and KDM6A genes in a group of healthy females who have various ethnic genetic backgrounds (“mixed”). No difference was observed in either XIST or KDM5C expression between the European Caucasian female controls and the female controls with various ethnic genetic backgrounds (Fig. 2E and F). A slightly higher level of KDM6A expression was observed in the controls with various ethnic backgrounds (Fig. S6C). Given that KDM6A expression varies between different cell cultures of the control samples (Fig. 1F vs Fig. 2D), it is not surprising that its expression was also affected by different ethnic backgrounds. We concluded that ethnic background has little effect on XIST and KDM5C expression. To enlarge the sample sizes of the psychiatric patients, we included more patients who have either bipolar disorder (mania and psychosis) or recurrent major depression with various ethnic backgrounds. Significant difference in either XIST or KDM5C expression was observed between the control group and each of the two patient groups (Fig. 3A and B). Since the same healthy European female Caucasians were used as a calibrator and control for analyses of all other control and patient groups, gene expression in each subject was therefore normalized against the group mean of the healthy European female Caucasians whose cells were co-cultured for quantification. There was a significantly larger variation of XIST expression between the combined control and the combined groups of either bipolar disorder (p = 8 × 10− 5, F-test) or major depression (p = 1 × 10− 10, F-test) (Fig. 3C). When both bipolar and major depression were combined (BP + MDR), a significantly larger variation was observed (p = 1 × 10− 8, F-test). Additionally, significant increase of XIST expression was also detected in bipolar (p = 1 × 10− 7), major depression (p = 0.004), and the combined (BP + MDR) group (p = 1 × 10− 7). Similarly, a larger variation of KDM5C expression was found in bipolar (p = 0.002, F-test), major depression (p = 0.004, F-test), and the combined (BP + MDR) group (p = 0.001, F-test) (Fig. 3D). Significant increase of KDM5C expression was also observed in bipolar disorder (p = 5.4 × 10− 6), major depression (p = 0.001), and the combined (BP + MDR) group (p = 5.3 × 10− 7). A high correlation was observed between XIST and KDM5C expression in all patients' cells (Pearson's coefficient, r = 0.78, p = 1.3 × 10− 13) (Fig. 4A). We explored whether a combination of XIST and KDM5C expression can be used as a potential diagnostic marker to separate the patients from the controls. According to calculation of reference range in clinical blood tests (William et al., 2008), we calculated the reference ranges of XIST and KDM5C expression in the control females to define a “normal” distribution. The upper limit of the reference range is defined as 2 standard deviations above the mean (dashed line, Fig. 4B). Out of 60 patients, 36 have XIST and/or KDM5C expression above their reference ranges. Among them, 20 patients have both XIST and KDM5C expressions above their reference ranges. None of the 36 controls display abnormally high XIST and/or KDM5C expression. Since it would be rare to have a control sample expressing both XIST and KDM5C above their reference ranges, we propose that a combination of both XIST and KDM5C gene expressions may serve as a reliable biological marker for diagnosis of bipolar disorder or major depression in a significantly large subset of female patients.

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