Epigenetic Markers For Development of Schizophrenia

描述（由申请人提供）：本拟议研究的目的是确定具有精神分裂症遗传高风险和/或前驱症状的人（HRSK受试者）的淋巴细胞中是否存在表观遗传相关生物标志物表达的差异，如先前在慢性精神分裂症（SZ）患者的淋巴细胞中发现的那样。我们还将评估这些生物标志物的存在是否预测哪些HRSK受试者将在两年内逐渐发展更多的精神病症状，以及哪些人将从HRSK状态转换为首发精神分裂症或其他可诊断的精神病性障碍。关于这一提议的研究人员已经与中国湖南的一组研究人员合作了几年（Wu等人，2008; 2012）。中国组目前正在进行一项由中国卫生部支持的多中心研究，涉及5000例HRSK和2000例对照受试者。我们提议的研究将是这项更大研究的补充。DNA甲基化和去甲基化是参与有丝分裂后神经元中特定基因转录的关键表观遗传组分（Guidotti等人，2011年）。已经表明，DNA甲基化/去甲基化过程在神经精神障碍如精神分裂症（SZ）、双相情感障碍（BP）和自闭症中受到干扰。我们已经表明，SZ患者脑中某些表观遗传标记的异常也存在于他们的淋巴细胞中。SZ患者的淋巴细胞的DNMT 1 mRNA表达高于非精神病对照（Zhubi et al 2009），其他甲基化和脱甲基化酶（生长停滞和DNA损伤诱导蛋白[GADD 45]和10 - 11易位蛋白[泰特]）水平较高，糖皮质激素受体和GAD 67 mRNA水平较低（初步数据）。如果这些潜在的表观遗传生物标志物的差异可以在HRSK受试者的淋巴细胞中得到证实，则可能会发现导致SZ的一些潜在的生化发育病理学。这一结果可以提供表观遗传生物标志物，用于预测HRSK受试者更有可能发展为SZ或相关精神病的全部症状。识别潜在的生物标志物将对预后和识别最有可能从强化早期干预和专门治疗中受益的患者产生影响。这一背景使我们对目前提出的研究追求三个具体目标：目标1：测量基线时HRSK受试者淋巴细胞中DNA甲基化相关基因的表达水平，与对照组和首次发作和慢性SZ患者相比。目标2：确定表观遗传染色质状态和SZ候选基因的表达是否受基线时HRSK受试者淋巴细胞中DNA甲基化/去甲基化途径组分蛋白质结合的调节，与对照组和首次发作和慢性SZ患者相比。目的3确定HRSK受试者在基线时也有表观遗传淋巴细胞异常是否更有可能进展为更严重的精神病样症状或在两年的随访期间转化为可诊断的精神病状态。这项拟议的研究可能是识别能够预测HRSK受试者转化为精神病的客观生物标志物的重要一步。

DESCRIPTION (provided by applicant): The goal of this proposed research is to determine whether differences in the expression of epigenetic related biomarkers are present in lymphocytes of people with genetic high risk and/or prodromal symptoms of schizophrenia (HRSK subjects) as previously found in lymphocytes of chronic schizophrenia (SZ) patients. We will also assess whether the presence of these biomarkers predicts which HRSK subjects will progressively develop more psychotic symptoms over a two year period and who will convert from HRSK status to first episode schizophrenia or another diagnosable psychotic disorder. Investigators on this proposal, have been collaborating with a group of investigators in Hunan, China for several years (Wu et al., 2008; 2012). The China group is currently conducting a multi-center study supported by the Chinese Ministry of Health that involves 5000 HRSK and 2000 control subjects. The research we are proposing would be an addendum to this larger study. DNA methylation and demethylation are key epigenetic components involved in orchestrating transcription of specific genes in post mitotic neurons (Guidotti et al., 2011). It has been suggested that the DNA methylation/demethylation process is perturbed in neuropsychiatric disorders such as schizophrenia (SZ), bipolar disorder (BP), and autism. We have shown that abnormalities in some of these epigenetic marks in the brain of SZ patients are also present in their lymphocytes. Lymphocytes of SZ patients have higher DNMT1 mRNA expression than non-psychotic controls (Zhubi et al 2009), higher levels of other methylating and demethylating enzymes (growth arrest and DNA damage-inducible protein [GADD45] and ten-eleven translocation protein [TET]), and lower levels of glucocorticoid receptor and GAD67 mRNA (preliminary data). If differences in these potential epigenetic biomarkers can be confirmed in lymphocytes of HRSK subjects, some of the underlying biochemical developmental pathology leading to SZ might be uncovered. This result could provide epigenetic biomarkers useful in predicting which HRSK subjects are more likely to develop full symptoms of SZ or a related psychosis. Identifying potential biomarkers would have implications for prognosis and identifying patients who would be most likely to benefit from intensive early intervention and specialized treatment. This background leads us to pursue three Specific Aims for the current proposed study: AIM1: Measure the expression level of DNA methylation related genes in lymphocytes of HRSK subjects at baseline compared to controls and first episode and chronic SZ patients. AIM 2: Determine whether epigenetic chromatin status and the expression of SZ candidate genes is regulated by the binding of proteins that are constituents of the DNA- methylation/demethylation pathways in lymphocytes of HRSK subjects at baseline compared to controls and first episode and chronic SZ patients. AIM 3 Determine whether HRSK subjects who also have epigenetic lymphocyte abnormalities at baseline are more likely to progress to more severe psychotic-like symptoms or convert to diagnosable psychotic status during a two year follow up. This proposed research is potentially a major step toward the identification of objective biomarkers capable of predicting conversion to psychosis in HRSK subjects.