Gosso Florencia M, de Geus Eco J C, Polderman Tinca J C, Boomsma Dorret I, Posthuma Danielle, Heutink Peter
Dept of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
BMC Med Genet. 2007 Nov 8;8:66. doi: 10.1186/1471-2350-8-66.
The CHRM2 gene, located on the long arm of chromosome 7 (7q31-35), is involved in neuronal excitability, synaptic plasticity and feedback regulation of acetylcholine release, and has been implicated in higher cognitive processing. The aim of this study is the identification of functional (non)coding variants underlying cognitive phenotypic variation.
We previously reported an association between polymorphisms in the 5'UTR regions of the CHRM2 gene and intelligence.. However, no functional variants within this area have currently been identified. In order to identify the relevant functional variant(s), we conducted a denser coverage of SNPs, using two independent Dutch cohorts, consisting of a children's sample (N = 371 ss; mean age 12.4) and an adult sample (N= 391 ss; mean age 37.6). For all individuals standardized intelligence measures were available. Subsequently, we investigated genotype-dependent CHRM2 gene expression levels in the brain, to explore putative enhancer/inhibition activity exerted by variants within the muscarinic acetylcholinergic receptor.
Using a test of within-family association two of the previously reported variants - rs2061174, and rs324650 - were again strongly associated with intelligence (P < 0.01). A new SNP (rs2350780) showed a trend towards significance. SNP rs324650, is located within a short interspersed repeat (SINE). Although the function of short interspersed repeats remains contentious, recent research revealed potential functionality of SINE repeats in a gene-regulatory context. Gene-expression levels in post-mortem brain material, however were not dependent on rs324650 genotype.
Using a denser coverage of SNPs in the CHRM2 gene, we confirmed the 5'UTR regions to be most interesting in the context of intelligence, and ruled out other regions of this gene. Although no correlation between genomic variants and gene expression was found, it would be interesting to examine allele-specific effects on CHRM2 transcripts expression in much more detail, for example in relation to transcripts specific halve-life and their relation to LTP and memory.
CHRM2基因位于7号染色体长臂（7q31 - 35），参与神经元兴奋性、突触可塑性及乙酰胆碱释放的反馈调节，并与高级认知加工有关。本研究旨在鉴定认知表型变异潜在的功能性（非）编码变体。
我们之前报道过CHRM2基因5'非翻译区（UTR）的多态性与智力之间的关联。然而，目前尚未在该区域鉴定出功能性变体。为了鉴定相关的功能性变体，我们使用了两个独立的荷兰队列对单核苷酸多态性（SNP）进行了更密集的覆盖，其中一个是儿童样本（N = 371例；平均年龄12.4岁），另一个是成人样本（N = 391例；平均年龄37.6岁）。所有个体均有标准化的智力测量数据。随后，我们研究了大脑中基因型依赖的CHRM2基因表达水平，以探索毒蕈碱型乙酰胆碱能受体内变体发挥的假定增强/抑制活性。
通过家系内关联检验，之前报道的两个变体——rs2061174和rs324650——再次与智力密切相关（P < 0.01）。一个新的SNP（rs2350780）显示出显著趋势。SNP rs324650位于一个短散在重复序列（SINE）内。尽管短散在重复序列的功能仍存在争议，但最近的研究揭示了SINE重复序列在基因调控背景下的潜在功能。然而，尸检脑材料中的基因表达水平并不依赖于rs324650基因型。
通过对CHRM2基因SNP进行更密集的覆盖，我们证实5'UTR区域在智力方面最为重要，并排除了该基因的其他区域。尽管未发现基因组变体与基因表达之间的相关性，但更详细地研究等位基因对CHRM2转录本表达特异性的影响将很有趣，例如与转录本特定半衰期及其与长时程增强和记忆的关系。
