DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia.
DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia.
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幼稚的精神分裂症患者中5-羟色胺转运蛋白基因启动子的DNA高甲基化。
DOI：
10.1016/j.schres.2013.12.007
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发表时间：
2014-03
影响因子：
4.5
通讯作者：
Thiagalingam S
中科院分区：
文献类型：
--
作者：
Abdolmaleky HM;Nohesara S;Ghadirivasfi M;Lambert AW;Ahmadkhaniha H;Ozturk S;Wong CK;Shafa R;Mostafavi A;Thiagalingam S
5-羟色胺信号失灵与自闭症、强迫症、情绪障碍和精神分裂症的发病机制有关。而5-羟色胺信号的低活性参与了抑郁症、焦虑症和强迫症的发病；5-羟色胺2型受体(5-HTR2A)激动剂LSD可诱发精神病。因此，焦虑和抑郁障碍是通过抑制5-羟色胺转运体(5-HTT)的SSRIs来治疗的，而精神病是通过阻断5-羟色胺和/或多巴胺受体的药物来控制的。鉴于5-HTT基因多态性和表观遗传异常参与了精神疾病的发病机制，我们分析了精神分裂症(SCZ)和双相情感障碍(BD)患者死后脑和唾液中5-HTT启动子的DNA甲基化，以探讨其作为诊断和/或治疗生物标志物在SCZ和BD中的潜在应用价值。使用Illumina 450K DNA甲基化阵列平台对总共24个样本(包括两个唾液样本)进行全基因组DNA甲基化分析，然后进行亚硫酸氢盐测序以确定候选CPGS以供进一步分析。应用定量甲基化特异性聚合酶链式反应(QMSP)检测105例死后脑组织(对照组35例，SCZ组35例，BD组35例)和100例唾液标本(对照组30例，SCZ组30例，BD组20例，SCZ或BD组20例)5-HTT启动子CpG甲基化程度。采用U1332.0Plus人转录组芯片，对30例(每组10例)死后脑组织标本进行5-HTT的定量实时定量聚合酶链式反应(RT-PCR)检测。5-HTT启动子区域的qMSP分析显示SCZ患者死后脑组织中DNA高甲基化(~30%)，尤其是在无药物患者(~60%，P=0.04)。类似地，在未服用抗精神病药物的BD患者中也有DNA高甲基化的趋势(~50%，p=0.066)。从唾液样本中提取的DNA的定量MSP分析还显示，SCZ患者5-HTT启动子高甲基化(~30%，p=0.039)，这在药物单纯的SCZ患者中更为明显(>；50%，p=0.0025)。然而，SCZ患者的对照组和未受影响的一级亲属(p=0.37)与使用抗精神病药物的患者(p=0.2)之间的差异并不显著。死后脑标本的全基因组转录组分析显示，5-HTT在SCZ患者中的表达低于对照组(~50%，p=0.008)，实时定量聚合酶链式反应分析(~40%，p=0.035)证实了这一点，在无药物治疗的SCZ患者(~70%，p=0.022)中更明显。药物朴素的SCZ患者5-HTT表达降低和5-HTT启动子DNA高甲基化之间的相关性表明，表观遗传学定义的5-HTT活性低下可能与SCZ的发病有关。此外，从唾液中提取的DNA中的这种表观遗传标记可以被认为是SCZ一系列诊断和/或治疗生物标记的关键决定因素之一。
Dysfunctional serotonin signaling has been linked to the pathogenesis of autism, obsessive compulsive disorder, mood disorders and schizophrenia. While the hypo-activity of serotonin signaling is involved in the pathogenesis of depression, anxiety and obsessive compulsive disorder; LSD, an agonist of serotonin type 2 receptor (5-HTR2A) induces psychosis. Therefore, anxiety and depressive disorders are treated by SSRIs which inhibit serotonin transporter (5-HTT) while psychotic disorders are controlled by drugs that block serotonin and/or dopamine receptors. Since genetic polymorphisms and epigenetic dysregulation of 5-HTT are involved in the pathogenesis of mental diseases, we analyzed DNA methylation of 5-HTT promoter in post-mortem brains and saliva samples of patients with schizophrenia (SCZ) and bipolar disorder (BD) to evaluate its potential application as a diagnostic and/or therapeutic biomarker in SCZ and BD. Whole genome DNA methylation profiling was performed for a total of 24 samples (including two saliva samples) using the Illumina 450K DNA methylation array platform, followed by bisulfite sequencing to identify candidate CpGs for further analysis. Quantitative methylation specific PCR (qMSP) was used to assess the degree of CpG methylation of 5-HTT promoter in 105 post-mortem brains (35 controls, 35 SCZ and 35 BD) and 100 saliva samples (30 controls, 30 SCZ, 20 BD and 20 first degree relatives of SCZ or BD). The U133 2.0 Plus Human Transcriptome array for a total of 30 post-mortem brain samples (each group 10) followed by quantitative real-time PCR was used to study 5-HTT expression in 105 post-mortem brain samples. The qMSP analysis for 5-HTT promoter region showed DNA hypermethylation in post-mortem brain samples of SCZ patients (~30%), particularly in drug free patients (~60%, p=0.04). Similarly, there was a trend for DNA hypermethylation in antipsychotic free BD patients (~50%, p=0.066). qMSP analysis of DNA extracted from the saliva samples also exhibited hypermethylation of 5-HTT promoter in patients with SCZ (~30%, p=0.039), which was more significant in drug naïve SCZ patients (>50%, p= 0.0025). However, the difference was not significant between the controls and unaffected first degree relatives of patients with SCZ (p=0.37) versus patients using antipsychotic drugs (p=0.2). The whole genome transcriptome analysis of post mortem brain samples showed reduced expression of 5-HTT in SCZ compared to the control subjects (~50%, p=0.008), confirmed by quantitative real-time PCR analysis (~40%, p=0.035) which was more significant in drug free SCZ patients (~70%, p=0.022). A correlation between reduction in 5-HTT expression and DNA hypermethylation of the 5-HTT promoter in drug naïve SCZ patients suggest that an epigenetically defined hypo-activity of 5-HTT may be linked to SCZ pathogenesis. Furthermore, this epigenetic mark in DNA extracted from saliva can be considered as one of the key determinants in a panel of diagnostic and/or therapeutic biomarkers for SCZ.
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DOI：
10.1002/ajmg.b.31192
发表时间：
2011-07-01
影响因子：
2.8
作者：
Ghadirivasfi, Mohammad;Nohesara, Shabnam;Abdolmaleky, Hamid Mostafavi
通讯作者：
Abdolmaleky, Hamid Mostafavi
DOI：
10.1073/pnas.0501509102
发表时间：
2005-04-12
影响因子：
11.1
作者：
Esaki, T;Cook, M;Holmes, A
通讯作者：
Holmes, A
影响因子：
15.1
作者：
Kinnally, Erin L.;Feinberg, Caroline;Kim, David;Ferguson, Kerel;Leibel, Rudolph;Coplan, Jeremy D.;Mann, J. John
通讯作者：
Mann, J. John
DOI：
10.1016/j.ajmg.b.30104
发表时间：
2005-02-05
影响因子：
2.8
作者：
Lasky-Su, JA;Faraone, SV;Tsuang, MT
通讯作者：
Tsuang, MT
DOI：
10.1002/ajmg.b.30132
发表时间：
2005-02-05
影响因子：
2.8
作者：
Feinn, R;Nellissery, M;Kranzler, HR
通讯作者：
Kranzler, HR