The serotonin-2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain
The serotonin-2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain
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DOI：
10.1038/sj.mp.4001366
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发表时间：
2004-01-01
影响因子：
11
通讯作者：
O'Donovan, MC
中科院分区：
文献类型：
--
作者：
Bray, NJ;Buckland, PR;O'Donovan, MC
5 -羟色胺- 2a （HTR2A）受体是生物精神病学中特别感兴趣的分子，因为它是精神药物的重要靶点（1,2），HTR2A表达的改变已在几种神经精神疾病中被发现，包括抑郁症(3)和精神分裂症(3)。(4)据报道，编码HTR2A基因的同义102T/C多态性与许多临床表型(包括精神分裂症、（5,6）氯氮平反应、（7)阿尔茨海默病的精神病症状(8)和抑郁症的某些特征）之间存在遗传关联。(9)鉴于目前还没有已知的102T/C多态性对受体结构的影响，人们的注意力转向了这样一种可能性，即对表达改变和遗传关联的观察表明，功能序列变异改变了HTR2A基因的表达。（10）此外，最近提出的数据表明，含有102T-和c -等位基因的mrna是差异表达的。（11）这表明变体本身对mRNA水平的直接影响，或者是一个独特的调控变体的影响，如-1438A/G启动子多态性，它与之处于完全的连锁不平衡状态。（12）本研究通过采用高度精确的定量等位基因特异性引物延伸试验（13）来测量23个102T/C多态性杂合个体中携带每个等位基因的脑mrna的相对表达量，从而验证了这一假设。通过比较基因组DNA和几个皮质区mRNA的等位基因比例，发现102C-和t等位基因表达相同。此外，相对mRNA等位基因比例的个体间差异的缺失表明，HTR2A位点不太可能包含改变成人大脑中HTR2A mRNA水平的常见多态性或表观遗传修饰，并且基本上排除了这些现象作为迄今为止报道的表达改变和遗传关联的潜在解释。
The serotonin-2A (HTR2A) receptor is a molecule of particular interest in biological psychiatry, as it is an important target for psychotropic drugs,(1,2) and altered HTR2A expression has been found in several neuropsychiatric conditions, including depression(3) and schizophrenia.(4) Genetic association has been reported between a synonymous 102T/C polymorphism in the gene encoding HTR2A and a number of clinical phenotypes, including schizophrenia,(5,6) clozapine response,(7) psychotic symptoms in Alzheimer's disease(8) and certain features of depression.(9) Given that there are no known effects of the 102T/C polymorphism on the structure of the receptor, attention has switched to the possibility that the observations of both altered expression and genetic association point to functional sequence variants that alter expression of the HTR2A gene.(10) Moreover, data have been presented recently suggesting that mRNAs containing the 102T- and C-alleles are differentially expressed.(11) This suggests a direct effect of the variant itself on mRNA levels, or the influence of a distinct regulatory variant, such as the -1438A/G promoter polymorphism, with which it is in perfect linkage disequilibrium.(12) The present study tested this hypothesis by employing a highly accurate quantitative allele-specific primer extension assay(13) to measure the relative expression of brain mRNAs carrying each allele in 23 individuals heterozygous for the 102T/C polymorphism. Comparison between allele ratios derived from genomic DNA and mRNA from several cortical regions revealed that the 102C- and T-alleles are expressed identically. Furthermore, the absence of any interindividual variability in relative mRNA allele ratio suggests that the HTR2A locus is unlikely to contain common polymorphisms or epigenetic modification that alter HTR2A mRNA levels in adult brain, and essentially exclude such phenomena as a potential explanation for the altered expression and genetic associations that have been reported to date.