Dominance Genetic Variation Contributes Little to the Missing Heritability for Human Complex Traits
Dominance Genetic Variation Contributes Little to the Missing Heritability for Human Complex Traits
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DOI：
10.1016/j.ajhg.2015.01.001
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发表时间：
2015-03-05
影响因子：
9.8
通讯作者：
Yang, Jian
中科院分区：
文献类型：
--
作者：
Zhu, Zhihong;Bakshi, Andrew;Yang, Jian
对于人类复杂的性状，非加性遗传变异被用来解释“缺失的遗传力”，但它的发现在全基因组关联研究中经常被忽视。本文提出了一种基于正交模型的方法，利用SNP数据对无关个体中所有SNP（h（SNP）（2）和delta（2）（SNP））的加性和显性遗传变异进行划分和估计，其中h（SNP）（2）的估计独立于delta（2）（SNP）的估计。用这种方法，我们分析了6,715名无关的欧洲裔美国人的79个数量性状。所有79个数量性状的平均delta（2）（SNP）估计值为0.03，约为加性变异的五分之一（平均h（SNP）（2）= 0.15）。有几个性状显示出delta（2）（SNP）的实质性估计，其中没有一个在11，965个个体的更大样本中重复。我们进一步对79个数量性状进行了全基因组关联分析，并检测到仅在因子VIII和血管性血友病因子的ABO基因座上具有全基因组显著显性效应的SNP。所有这些结果表明，在常见的SNPs的显性变异只能解释一小部分的人类复杂性状的表型变异，并没有贡献失踪的狭义遗传力问题。
For human complex traits, non-additive genetic variation has been invoked to explain "missing heritability,'' but its discovery is often neglected in genome-wide association studies. Here we propose a method of using SNP data to partition and estimate the proportion of phenotypic variance attributed to additive and dominance genetic variation at all SNPs (h(SNP)(2) and delta(2)(SNP)) in unrelated individuals based on an orthogonal model where the estimate of h(SNP)(2) is independent of that of delta(2)(SNP). With this method, we analyzed 79 quantitative traits in 6,715 unrelated European Americans. The estimate of delta(2)(SNP) averaged across all the 79 quantitative traits was 0.03, approximately a fifth of that for additive variation (average h(SNP)(2) = 0.15). There were a few traits that showed substantial estimates of delta(2)(SNP), none of which were replicated in a larger sample of 11,965 individuals. We further performed genome-wide association analyses of the 79 quantitative traits and detected SNPs with genome-wide significant dominance effects only at the ABO locus for factor VIII and von Willebrand factor. All these results suggest that dominance variation at common SNPs explains only a small fraction of phenotypic variation for human complex traits and contributes little to the missing narrow-sense heritability problem.