Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Nat Genet. 2010 Jul;42(7):565-9. doi: 10.1038/ng.608. Epub 2010 Jun 20.
SNPs discovered by genome-wide association studies (GWASs) account for only a small fraction of the genetic variation of complex traits in human populations. Where is the remaining heritability? We estimated the proportion of variance for human height explained by 294,831 SNPs genotyped on 3,925 unrelated individuals using a linear model analysis, and validated the estimation method with simulations based on the observed genotype data. We show that 45% of variance can be explained by considering all SNPs simultaneously. Thus, most of the heritability is not missing but has not previously been detected because the individual effects are too small to pass stringent significance tests. We provide evidence that the remaining heritability is due to incomplete linkage disequilibrium between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency than the SNPs explored to date.
全基因组关联研究 (GWAS) 发现的单核苷酸多态性 (SNP) 仅占人类群体中复杂性状遗传变异的一小部分。其余的遗传率在哪里?我们使用线性模型分析,对 3925 名无亲缘关系个体中 294831 个 SNP 的基因型进行了分析,估计了人类身高的方差比例,并基于观察到的基因型数据进行了模拟验证。我们表明,同时考虑所有 SNP 可以解释 45%的方差。因此,大部分遗传率并没有缺失,只是以前没有被检测到,因为个体效应太小,无法通过严格的显著性检验。我们提供的证据表明,剩余的遗传率是由于因果变异与已检测 SNP 之间不完全连锁不平衡所致,这是由因果变异的次要等位基因频率低于迄今为止探索的 SNP 所加剧的。
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