Beijing Institute of Brain Disorders, Capital Medical University, Beijing 100069, China; Advanced Innovation Center for Brain Disorders, Capital Medical University, Beijing 100069, China.
Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, China.
Compr Psychiatry. 2019 Oct;94:152121. doi: 10.1016/j.comppsych.2019.152121. Epub 2019 Aug 19.
Methylenetetrahydrofolate reductase (MTHFR) is the critical enzyme in biotransformation. The polymorphism of MTHFR is a risk factor for schizophrenia. However, whether the MTHFR polymorphism is associated with schizophrenia disease phenotypes and what is the underlying mechanism of MTHFR polymorphism in schizophrenia is under-investigated. In this study, we aim to verify the correlation between MTHFR polymorphisms and clinical features of schizophrenia, while exploring the differential genomic methylation and disease related genes as the potential targets for schizophrenia.
242 patients of schizophrenia and 234 matched healthy controls were enrolled in this study. Polymorphisms of MTHFR from three sites (C677T, A1298C, G1793A) were examined by Taqman fluorescence probe method in leukocytes from all subjects. The positive and negative syndrome scale (PANSS), trail making test (TMT) and Clinical Global Impression (CGI) were checked on patients. Genomic methylation was tested and analyzed in fields of differential methylation positions (DMPs) and enrichment of genes that are potentially related to schizophrenia.
Schizophrenic patients showed higher frequency of MTHFR polymorphisms at both single and multiple sites than healthy controls. Our data also showed that MTHFR C677T and multiple-site polymorphisms were positively correlated with PANSS positive rating, not negative score in male schizophrenia patients. Furthermore, while a significant reduction of global DNA methylation level was observed in schizophrenic patients, we also identified several genes which differentiated between schizophrenia and healthy controls at methylation levels.
This is a pilot study revealing that MTHFR polymorphisms at both single and multiple sites are related to the risk of schizophrenia and positive symptom of the disease. The risk of MTHFR polymorphism in schizophrenia and the clinical symptoms was only significant in male patients. While the sex-specific risk of MTHFR in schizophrenia is new and the reasons remain unanswered. Our methylation analysis suggested that there was significant hypomethylation of genomic DNA in schizophrenia patients with no sex difference. The correlation between MTHFR polymorphism and schizophrenia may attribute to the change of DNA methylation level, and some certain genes could be potential research objects for MTHFR effects on schizophrenia.
亚甲基四氢叶酸还原酶（MTHFR）是生物转化的关键酶。MTHFR 多态性是精神分裂症的危险因素。然而，MTHFR 多态性是否与精神分裂症疾病表型相关，以及 MTHFR 多态性在精神分裂症中的潜在机制是什么，这些问题还没有得到充分的研究。在这项研究中，我们旨在验证 MTHFR 多态性与精神分裂症临床特征之间的相关性，同时探索差异基因组甲基化和疾病相关基因作为精神分裂症的潜在靶点。
本研究纳入了 242 例精神分裂症患者和 234 名匹配的健康对照者。采用 Taqman 荧光探针法检测所有受试者白细胞中 MTHFR 的三个位点（C677T、A1298C、G1793A）的多态性。对患者进行阳性和阴性症状量表（PANSS）、连线测试（TMT）和临床总体印象量表（CGI）评估。对差异甲基化位置（DMPs）和可能与精神分裂症相关的基因富集进行基因组甲基化检测和分析。
精神分裂症患者的 MTHFR 单核苷酸多态性和多位点多态性频率均高于健康对照组。我们的数据还显示，MTHFR C677T 及多位点多态性与男性精神分裂症患者的 PANSS 阳性评分呈正相关，与阴性评分无关。此外，虽然精神分裂症患者的全基因组 DNA 甲基化水平显著降低，但我们还在甲基化水平上鉴定了一些区分精神分裂症患者和健康对照组的基因。
这是一项初步研究，表明 MTHFR 单核苷酸多态性和多位点多态性与精神分裂症的发病风险和阳性症状有关。MTHFR 多态性在精神分裂症及临床症状中的风险仅在男性患者中显著。而 MTHFR 在精神分裂症中存在性别特异性风险是新的发现，其原因尚不清楚。我们的甲基化分析表明，精神分裂症患者的基因组 DNA 存在显著的低甲基化，且无性别差异。MTHFR 多态性与精神分裂症的相关性可能归因于 DNA 甲基化水平的变化，某些特定基因可能是 MTHFR 对精神分裂症影响的潜在研究对象。
