Butcher Lee M, Meaburn Emma, Knight Jo, Sham Pak C, Schalkwyk Leonard C, Craig Ian W, Plomin Robert
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK.
Hum Mol Genet. 2005 May 15;14(10):1315-25. doi: 10.1093/hmg/ddi142. Epub 2005 Mar 30.
Mild mental impairment (MMI) represents the low extreme of the quantitative trait of general intelligence and is highly heritable. Quantitative trait loci (QTLs) conferring susceptibility to MMI, as for most complex traits, are likely to be of small effect size. Using a novel approach we call SNP-MaP (SNP Microarrays and Pooling), we have identified four loci associated with MMI. These four loci have been replicated in two SNP-MaP studies and verified by individual genotyping. The two SNP-MaP studies conducted were a case versus control comparison (n = 515 and n = 1028, respectively) and a low versus high general intelligence extremes group comparison (n = 503 and n = 505, respectively). Each of the four groups consisted of five independent 'subpools', with each subpool assayed on a separate microarray. Twelve loci showing the largest significant differences in both SNP-MaP studies were individually genotyped on 6154 children. Of the four loci positively associated with MMI, the minor allele of each conferred the greater risk for MMI. Two of the loci are close to known genes and may be in linkage disequilibrium with them. One of the loci is between the candidate genes KLF7 and CREB1, but given possible long-range effects on expression and the unknown importance of untranslated elements such as micro-RNAs, all four loci deserve attention as candidates. Although each SNP accounts for a small amount of variance, their effects are additive and they can be combined in a 'SNP set' that can be used as a genetic risk index for MMI in behavioral genomic analyses.
轻度智力损害(MMI)代表一般智力数量性状的低极端情况,且具有高度遗传性。与大多数复杂性状一样,赋予MMI易感性的数量性状基因座(QTL)可能效应大小较小。我们使用一种称为SNP-MaP(SNP微阵列与混合法)的新方法,已鉴定出四个与MMI相关的基因座。这四个基因座已在两项SNP-MaP研究中得到重复,并通过个体基因分型得到验证。所进行的两项SNP-MaP研究分别是病例与对照比较(分别为n = 515和n = 1028)以及一般智力低极端组与高极端组比较(分别为n = 503和n = 505)。四个组中的每组均由五个独立的“子池”组成,每个子池在单独的微阵列上进行检测。在两项SNP-MaP研究中显示出最大显著差异的12个基因座在6154名儿童中进行了个体基因分型。在与MMI呈正相关的四个基因座中,每个基因座的次要等位基因赋予MMI更大的风险。其中两个基因座靠近已知基因,可能与它们处于连锁不平衡状态。其中一个基因座位于候选基因KLF7和CREB1之间,但考虑到对表达可能存在的远距离效应以及诸如微小RNA等非翻译元件的未知重要性,所有四个基因座都值得作为候选基因加以关注。尽管每个SNP仅解释少量变异,但其效应是累加的,并且它们可以组合成一个“ SNP集”,在行为基因组分析中用作MMI的遗传风险指数。