Bray N J, Buckland P R, Hall H, Owen M J, O'Donovan M C
Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Mol Psychiatry. 2004 Jan;9(1):109-14. doi: 10.1038/sj.mp.4001366.
The serotonin-2A (HTR2A) receptor is a molecule of particular interest in biological psychiatry, as it is an important target for psychotropic drugs, and altered HTR2A expression has been found in several neuropsychiatric conditions, including depression and schizophrenia. Genetic association has been reported between a synonymous 102T/C polymorphism in the gene encoding HTR2A and a number of clinical phenotypes, including schizophrenia, clozapine response, psychotic symptoms in Alzheimer's disease and certain features of depression. 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. Moreover, data have been presented recently suggesting that mRNAs containing the 102T- and C-alleles are differentially expressed. 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. The present study tested this hypothesis by employing a highly accurate quantitative allele- specific primer extension assay 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.
血清素2A（HTR2A）受体是生物精神病学中特别受关注的分子，因为它是精神药物的重要靶点，并且在包括抑郁症和精神分裂症在内的多种神经精神疾病中发现HTR2A表达发生改变。据报道，编码HTR2A的基因中一个同义的102T/C多态性与多种临床表型相关，包括精神分裂症、氯氮平反应、阿尔茨海默病中的精神病症状以及抑郁症的某些特征。鉴于102T/C多态性对受体结构没有已知影响，注意力已转向这样一种可能性，即表达改变和基因关联的观察结果指向改变HTR2A基因表达的功能性序列变异。此外，最近有数据表明，含有102T和C等位基因的mRNA存在差异表达。这表明该变异本身对mRNA水平有直接影响，或者是一个不同的调控变异（如-1438A/G启动子多态性）的影响，它与该变异处于完全连锁不平衡状态。本研究通过采用一种高度准确的定量等位基因特异性引物延伸测定法来测量23名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，对这一假设进行了检验。来自几个皮质区域的基因组DNA和mRNA的等位基因比率比较显示，102C和T等位基因的表达相同。此外，相对mRNA等位基因比率不存在个体间差异，这表明HTR2A基因座不太可能包含改变成人大脑HTR2A mRNA水平的常见多态性或表观遗传修饰，并基本上排除了这些现象作为迄今为止报道的表达改变和基因关联的潜在解释。
