RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity.
RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity.
复制标题
死后人类皮质中的 RGS4 mRNA 表达与 COMT Val158Met 基因型和 COMT 酶活性相关。
DOI：
10.1093/hmg/ddl222
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发表时间：
2006
影响因子：
3.5
通讯作者：
Kleinman,JoelE
中科院分区：
文献类型：
--
作者：
Lipska,BarbaraK;Mitkus,Shruti;Caruso,Mark;Hyde,ThomasM;Chen,Jingshan;Vakkalanka,Radhakrishna;Straub,RichardE;Weinberger,DanielR;Kleinman,JoelE
连锁、关联和死后研究表明，g蛋白信号传导4 （RGS4）的调节因子是一种候选的精神分裂症易感基因，它可以负向调节g蛋白偶联受体的信号转导。我们比较了两个独立队列（CBDB/NIMH Collection和Stanley Array Collection）中正常对照组和精神分裂症患者背外侧前额叶皮质（DLPFC）中RGS4 mRNA的表达，以及CBDB/NIMH Collection中海马中的RGS4 mRNA表达。我们还研究了先前确定的四个RGS4风险snp （rs10917670, rs951436, rs951439, rs2661319）对这些队列中RGS4表达水平的影响。由于多巴胺信号与RGS4表达有关，且COMT Val158Met多态性与RGS4等位基因之间存在统计学上的上位性，因此我们还研究了COMT Val158Met基因型与DLPFC中RGS4表达之间的关系。我们没有发现精神分裂症患者（或Stanley Collection中的双相情感障碍患者）和对照组之间RGS4表达水平的差异，也没有发现任何RGS4风险snp与RGS4表达之间的显著关联。然而，COMT Val158Met基因型以等位基因剂量依赖的方式与前额叶和海马RGS4 mRNA表达相关，COMT Val等位基因携带者的表达明显低于Met等位基因的杂合个体或纯合受试者。与这些基因型效应一致，RGS4 mRNA与DLPFC中COMT酶活性呈负相关。这些数据表明RGS4 mRNA表达与皮质多巴胺信号传导有关，并说明遗传和/或环境背景在精神分裂症基因表达研究中的重要性。
Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose-dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia.