Association analysis of mild mental impairment using DNA pooling to screen 432 brain-expressed single-nucleotide polymorphisms
Association analysis of mild mental impairment using DNA pooling to screen 432 brain-expressed single-nucleotide polymorphisms
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DOI：
10.1038/sj.mp.4001589
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发表时间：
2005-04-01
影响因子：
11
通讯作者：
Plomin, R
中科院分区：
文献类型：
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作者：
Butcher, LM;Meaburn, E;Plomin, R
我们假设轻度精神障碍（MMI）代表了在整个智力分布中运作的相同数量性状位点（qtl）的低端。为了检测小效应量的qtl，我们采用直接关联策略，从288例病例和1025例对照的DNA池的公共数据库中鉴定出432个可能具有功能的非同义单核苷酸多态性（nssnp）进行基因分型。通过麦卡锡儿童能力量表的家庭管理，共有288例MMI病例被确定为836对双胞胎，这些双胞胎是从1.4万多名儿童的社区样本中选出的，之前通过父母管理的测试筛选了非语言认知延迟。对照组是从社区样本中选出的，代表了非语言智力的全部范围。在病例和对照DNA库之间显示至少7%等位基因频率差异的snp使用五个DNA子库进行测试，以确定它们与非语言智力的全范围关联，每个子库代表1025个对照正常数量性状得分的五分之一。对288例病例和1025例对照进行基因分型，并使用标准统计方法进行分析。HSPA8中的一个SNP （rs1136141）符合这些标准，在个体基因分型中，病例和对照组之间的等位基因频率差异显著（P = 0.036），对照组内的相关性显著（P = 0.013），占方差的0.5%。目前的SNP策略与DNA池和大样本相结合，代表了在后基因组时代识别与复杂性状相关的小效应大小的qtl的一步，届时所有功能多态性都将被知道。
We hypothesize that mild mental impairment (MMI) represents the low extreme of the same quantitative trait loci (QTLs) that operate throughout the distribution of intelligence. To detect QTLs of small effect size, we employed a direct association strategy by genotyping 432 presumably functional nonsynonymous single-nucleotide polymorphisms (nsSNPs) identified from public databases on DNA pools of 288 cases and 1025 controls. In total, 288 MMI cases were identified by in-home administration of McCarthy Scales of Children's Abilities to 836 twin pairs selected from a community sample of more than 14 000 children previously screened for nonverbal cognitive delay using parentally administered tests. Controls were selected from the community sample representing the full range of nonverbal intelligence. SNPs showing at least 7% allele frequency differences between case and control DNA pools were tested for their association with the full range of nonverbal intelligence using five DNA subpools, each representing quintiles of the normal quantitative trait scores from the 1025 controls. SNPs showing linear associations in the expected direction across quintiles using pooled DNA were individually genotyped for the 288 cases and 1025 controls and analyzed using standard statistical methods. One SNP (rs1136141) in HSPA8 met these criteria, yielding a significant ( P = 0.036) allelic frequency difference between cases and controls for individual genotyping and a significant ( P = 0.013) correlation within the control group that accounts for 0.5% of the variance. The present SNP strategy combined with DNA pooling and large samples represents a step towards identifying QTLs of small effect size associated with complex traits in the postgenomic era when all functional polymorphisms will be known.