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 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. A 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. First, 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. The 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. Our 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.

中文翻译：

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女性精神分裂症的一种新的性别特异性潜在机制：加速倾斜的 X 染色体失活。

X 染色体失活 (XCI) 是在性别之间调整 X 连锁基因剂量的机制。有证据表明，许多性别特异性疾病都以 X 染色体生物学为基础。虽然女性精神分裂症患者的发病年龄往往较晚，临床表型与男性不同，但尚不清楚精神分裂症的性别差异是否与 X 连锁基因剂量和女性细胞中 X 染色体沉默的选择有关。 . 以往的研究表明，性染色体非整倍体可能与一些精神疾病的发病机制有关。在这里，我们检查了精神分裂症患者偏斜 XCI 的变化。本研究共包括 109 名女性精神分裂症 (SCZ) 患者和 80 名年龄和性别匹配的健康对照 (CNTL)。我们评估了临床特征，包括疾病发病年龄、疾病持续时间、阳性和阴性综合征量表 (PANSS) 的临床症状和抗精神病药治疗剂量。XCI 偏斜模式通过从三个年龄组的 SCZ 患者和 CNTL 白细胞中分离的 DNA 中发现的 HUMAR 基因的甲基化谱进行分析。首先，我们发现 SCZ 患者的偏斜 XCI 频率是年龄和性别匹配的 CNTL 的 4 倍（p < 0.01）。其次，我们发现 SCZ 患者比 CNTL 更早发生严重的 XCI 偏斜。第三，我们证明了偏斜 XCI 的严重程度与精神分裂症症状（PANSS 评分 ≥ 90）以及发病年龄之间存在密切关系。第四，我们证明了 SCZ 患者中倾斜的 XCI 不是从患者的母亲那里传播的。XCI 偏斜模式可能因组织或器官而异。尽管这是第一项探索 SCZ 中偏斜 XCI 的研究，但将来，来自 SCZ 患者不同组织或细胞的样本可能对于了解偏斜 XCI 在该疾病中的影响很重要。我们的研究首次调查了女性 SCZ 患者的偏斜 XCI，并提出了 SCZ 性别差异的潜在机制。我们的数据还表明 XCI 可能是开发针对 SCZ 的女性特定干预措施的潜在目标。研究了女性 SCZ 患者的偏斜 XCI，并提出了 SCZ 性别差异的潜在机制。我们的数据还表明 XCI 可能是开发针对 SCZ 的女性特定干预措施的潜在目标。研究了女性 SCZ 患者的偏斜 XCI，并提出了 SCZ 性别差异的潜在机制。我们的数据还表明 XCI 可能是开发针对 SCZ 的女性特定干预措施的潜在目标。