Abstract
BackgroundX chromosome inactivation (XCI) is the mechanism by which the X-linked gene dosage is adjusted between the sexes. Evidence shows that many sex-specific diseases have their basis in X chromosome biology. While female schizophrenia patients often have a delayed age of disease onset and clinical phenotypes that are different from those of males, it is unknown whether the sex differences in schizophrenia are associated with X-linked gene dosage and the choice of X chromosome silencing in female cells. Previous studies demonstrated that sex chromosome aneuploidies may be related to the pathogeneses of some psychiatric diseases. Here, we examined the changes in skewed XCI in patients with schizophrenia.MethodsA total of 109 female schizophrenia (SCZ) patients and 80 age- and sex-matched healthy controls (CNTLs) were included in this study. We evaluated clinical features including disease onset age, disease duration, clinical symptoms by the Positive and Negative Syndrome Scale (PANSS) and antipsychotic treatment dosages. The XCI skewing patterns were analyzed by the methylation profile of the HUMARA gene found in DNA isolated from SCZ patient and CNTL leukocytes in the three age groups.ResultsFirst, we found that the frequency of skewed XCI in SCZ patients was 4 times more than that in the age- and sex-matched CNTLs (p < 0.01). Second, we found an earlier onset of severe XCI skewing in the SCZ patients than in CNTLs. Third, we demonstrated a close relationship between the severity of skewed XCI and schizophrenic symptoms (PANSS score ≥ 90) as well as the age of disease onset. Fourth, we demonstrated that the skewed XCI in SCZ patients was not transmitted from the patients’ mothers.LimitationsThe XCI skewing pattern might differ depending on tissues or organs. Although this is the first study to explore skewed XCI in SCZ, in the future, samples from different tissues or cells in SCZ patients might be important for understanding the impact of skewed XCI in this disease.ConclusionOur study, for the first time, investigated skewed XCI in female SCZ patients and presented a potential mechanism for the sex differences in SCZ. Our data also suggested that XCI might be a potential target for the development of female-specific interventions for SCZ.
Highlights
Schizophrenia (SCZ) is a chronic brain disorder with great physical morbidity and high mortality [1]
To explore the linkage between X chromosome inactivation (XCI) skewing and SCZ, the aims of the present study were as follows: (1) to investigate XCI skewing in patients with SCZ or major depressive disorder (MDD) and age-matched controls (CNTLs); (2) to identify the association between clinical symptom severity and the degree of skewed XCI in SCZ patients; (3) to study age-related changes in XCI skewing in young, middle-aged and elderly female SCZ patients and compare them with those of matched CNTLs; and (4) to explore whether skewed XCI in SCZ children is transmitted from parents
Higher frequency of severe XCI skewing in schizophrenia patients After excluding 6 patients who were homozygous at the CAG locus, there were 147 patients with psychiatric disease (109 SCZ patients and 38 MDD patients) and 80 CNTLs for whom the degree of XCI skewing was analyzed
Summary
Schizophrenia (SCZ) is a chronic brain disorder with great physical morbidity and high mortality [1]. Whether the X chromosome plays any role in the sex-specific differences in SCZ is unknown. Many genes associated with psychiatric diseases, including SCZ, are located on the X chromosome [4,5,6]. X chromosome inactivation (XCI) is the mechanism by which the X-linked gene dosage is adjusted between the sexes. Evidence shows that many sex-specific diseases have their basis in X chromosome biology. While female schizophrenia patients often have a delayed age of disease onset and clinical phenotypes that are different from those of males, it is unknown whether the sex differences in schizophrenia are associated with Xlinked gene dosage and the choice of X chromosome silencing in female cells. We examined the changes in skewed XCI in patients with schizophrenia
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