Increased gene expression of diacylglycerol kinase η in bipolar disorder.
Increased gene expression of diacylglycerol kinase η in bipolar disorder.
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双相情感障碍中二酰甘油激酶 δ 基因表达增加。
DOI：
10.1017/s1461145710000593
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发表时间：
2010
期刊：
影响因子：
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通讯作者：
Wendland,JensR
中科院分区：
文献类型：
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作者：
Moya,PabloR;Murphy,DennisL;McMahon,FrancisJ;Wendland,JensR
双相情感障碍(BD)是一种高度可遗传的神经精神疾病，以反复发作的抑郁、躁狂或轻躁为特征。最近对BD的全基因组关联研究提出了新的候选基因，包括编码二酰基甘油激酶η亚型的基因(DGKH；Baum等。2008a)。该基因与BD的关联在撒丁岛样本的单倍型水平上被复制(Squassina等人。2009)，但不是针对单个SNP，也不是作为锂反应的预测指标(Manchia等人。2009年)。二酰甘油激酶(DGK)调节细胞内二酰甘油的浓度，二酰甘油是主要抗BD药物锂靶向的肌醇信号系统的主要成分(Van Blitterswjk等人综述)。2000；另见Harwood，2005，关于肌醇消耗假说以及锂和BD的讨论)。DGKH在大脑中高度表达，也是糖皮质激素诱导的和压力反应的(Klauck等人。1996年；Murakami et al.2003年)。在此，我们提出了DGKH基因在BD中表达增加的证据。我们通过实时定量聚合酶链式反应对斯坦利医学研究所捐赠的100个死后脑组织样本中的DGKH mRNA进行了量化。所有样本均来自BD组(n=31)、精神分裂症组(n=35)和正常对照组(n=34)。在前面描述的扩增条件下，我们使用了TGA CAG CAC AGA AAC AGA TGA AT和GGA GAC CGA GGT GCA GTT T以及荧光探针(通用探针库编号69，罗氏应用科学，美国)。2009年)。实验是在样本代码被破解后进行的，因此他们没有失明。使用G*Power 3.1版。2(Faul et al.2007)，在固定效应综合方差分析中，我们确定我们的样本对中等效应大小(f=0.25)有一定的检测能力(56%)，对大效应大小(f=0.4)有很好的检测能力(94%)。整个数据集已上传到斯坦利医学研究所数据库(http://www.斯坦利研究公司。组织/大脑)。我们没有对上传到该数据库的所有可比表达遗传学研究应用多重测试校正。所有实验都是在马里兰州贝塞斯达的国家精神卫生研究所内部研究计划部门的机构审查委员会批准的方案下进行的。单因素方差分析显示，三组间DGKH基因表达水平差异有统计学意义(F2，97=4.44，p=0.01)。如图1所示，BD样本显示DGKH水平显著升高(Tukey‘s Post<；分析，p<；0.05)，BD患者的平均表达水平比对照组高约25%。我们还量化了两个已知的DGKH转录变体(Murakami等人。2003年)，但没有观察到显著的差异；此外，我们也没有观察到显著的性别或年龄效应(数据未显示)。在荟萃分析中，我们对所有样本进行了基因组DGKH基因座rs1170191和rs1012053中两个SNP的基因分型，这两个SNP仍然与BD相关(Baum等人。2008b)。在三个诊断组之间，两个SNPs的等位基因和基因频率没有显著差异。即使在将诊断作为协变量纳入后，也没有发现任何一个SNP与DGKH信使核糖核酸水平相关(数据未显示)。提示DGKH基因表达增加参与了BD的发病机制。有趣的是，BD障碍组与精神分裂症组没有显著差异(尽管后者有…
Bipolar disorder (BD) is a highly heritable neuropsychiatric illness characterized by recurrent episodes of depression and mania or hypomania. Recent genomewide association studies of BD have proposed novel candidates, including the gene encoding the η isoform of diacylglycerol kinase (DGKH; Baum et al. 2008a). The association of this gene with BD was replicated at the haplotype level in a Sardinian sample (Squassina et al. 2009), but not for individual SNPs or as a predictor of lithium response (Manchia et al. 2009). Diacylglycerol kinase (DGK) regulates the intracellular concentration of diacylglycerol, which is a main component of inositol signalling systems targeted by the major anti-BD agent, lithium (reviewed in van Blitterswijk et al. 2000; see also Harwood, 2005, for discussion of the inositol-depletion hypothesis and lithium and BD). DGKH is highly expressed in brain and is also glucocorticoid-inducible and stressresponsive (Klauck et al. 1996; Murakami et al. 2003). Here, we present evidence that gene expression of DGKH is increased in BD. We quantified DGKH mRNA by real-time quantitative polymerase chain reaction in a collection of 100 post-mortem brain-tissue samples donated by The Stanley Medical Research Institute. All samples were derived from the dorsolateral prefrontal cortex and originated from three diagnostic groups: BD (n= 31), schizophrenia (n= 35) and unaffected controls (n= 34). We used intron-spanning primers TGA CAG CAC AGA AAC AGA TGA AT and GGA GAC CGA GGT GCA GTT T as well as a fluorescent probe (Universal Probe Library no. 69, Roche Applied Science, USA) under amplification conditions described previously (Wendland et al. 2009). Experiments were done after the specimen code was broken and they were thus unblinded. Using G* Power version 3.1. 2 (Faul et al. 2007), we determined our sample had some power (56%) to detect medium effect sizes (f= 0.25) and excellent power (94%) for large effect sizes (f= 0.4) in a fixed-effects omnibus analysis of variance test. The entire dataset has been uploaded to The Stanley Medical Research Institute databank (http://www. stanleyresearch. org/brain). We did not apply multiple testing correction for all comparable expression genetics studies uploaded to this databank. All experiments were conducted under protocols approved by the Institutional Review Board of the National Institute of Mental Health Division of Intramural Research Programs in Bethesda, MD. One-way analysis of variance showed that the three diagnostic groups differed significantly in their DGKH mRNA expression levels (F2, 97= 4.44, p= 0.01). As shown in Fig. 1, BD samples displayed significantly increased DGKH levels (Tukey’s post-hoc analysis, p< 0.05), with the mean expression level being about 25% higher in BD than in controls. We also quantified two known DGKH transcript variants (Murakami et al. 2003) with transcript-specific probes but did not observe significant differences; moreover, we did not observe significant sex or age effects (data not shown). We genotyped all samples for two SNPs within the genomic DGKH locus, rs1170191 and rs1012053, that remained associated with BD in a meta-analysis (Baum et al. 2008b). Allelic and genotypic frequencies did not significantly differ between the three diagnostic groups for both SNPs. There was no association of either SNP with DGKH mRNA levels, even after inclusion of diagnosis as covariate (data not shown). Our data suggest that increased gene expression of DGKH is involved in the pathogenesis of BD. Interestingly, the BD disorder group did not differ significantly from the schizophrenia group (although the latter …