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利用混合DNA和50万个单核苷酸多态性微阵列对一般认知能力进行全基因组数量性状位点关联扫描。

Genome-wide quantitative trait locus association scan of general cognitive ability using pooled DNA and 500K single nucleotide polymorphism microarrays.

作者信息

Butcher L M, Davis O S P, Craig I W, Plomin R

机构信息

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.

出版信息

Genes Brain Behav. 2008 Jun;7(4):435-46. doi: 10.1111/j.1601-183X.2007.00368.x. Epub 2008 Jan 22.

Abstract

General cognitive ability (g), which refers to what cognitive abilities have in common, is an important target for molecular genetic research because multivariate quantitative genetic analyses have shown that the same set of genes affects diverse cognitive abilities as well as learning disabilities. In this first autosomal genome-wide association scan of g, we used a two-stage quantitative trait locus (QTL) design with pooled DNA to screen more than 500,000 single nucleotide polymorphisms (SNPs) on microarrays, selecting from a sample of 7000 7-year-old children. In stage 1, we screened for allele frequency differences between groups pooled for low and high g. In stage 2, 47 SNPs nominated in stage 1 were tested by individually genotyping an independent sample of 3195 individuals, representative of the entire distribution of g scores in the full 7000 7-year-old children. Six SNPs yielded significant associations across the normal distribution of g, although only one SNP remained significant after a false discovery rate of 0.05 was imposed. However, none of these SNPs accounted for more than 0.4% of the variance of g, despite 95% power to detect associations of that size. It is likely that QTL effect sizes, even for highly heritable traits such as cognitive abilities and disabilities, are much smaller than previously assumed. Nonetheless, an aggregated 'SNP set' of the six SNPs correlated 0.11 (P < 0.00000003) with g. This shows that future SNP sets that will incorporate many more SNPs could be useful for predicting genetic risk and for investigating functional systems of effects from genes to brain to behavior.

摘要

一般认知能力(g)指的是各种认知能力的共同之处,它是分子遗传学研究的一个重要目标,因为多变量定量遗传分析表明,同一组基因会影响多种认知能力以及学习障碍。在这项首次针对g的常染色体全基因组关联扫描中,我们采用了两阶段定量性状基因座(QTL)设计,利用混合DNA在微阵列上筛选了超过50万个单核苷酸多态性(SNP),样本来自7000名7岁儿童。在第一阶段,我们筛选了低g组和高g组混合样本之间的等位基因频率差异。在第二阶段,对第一阶段提名的47个SNP进行了单独基因分型检测,样本为3195名个体,代表了7000名7岁儿童g分数的整个分布情况。在g的正态分布中,有6个SNP产生了显著关联,不过在设定错误发现率为0.05后,只有1个SNP仍具有显著性。然而,尽管有95% 的把握检测到那个水平的关联,但这些SNP中没有一个能解释超过0.4% 的g方差。即便对于认知能力和障碍这类高度可遗传的性状,QTL效应大小可能也比之前设想的要小得多。尽管如此,这6个SNP的一个聚合 “SNP集” 与g的相关性为0.11(P < 0.00000003)。这表明,未来纳入更多SNP的SNP集可能有助于预测遗传风险以及研究从基因到大脑再到行为的效应功能系统。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/117b/2408663/18e1f1104a1b/gbb0007-0435-f1.jpg

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