Contribution of an additive locus to genetic variance when inheritance is multi-factorial with implications on interpretation of GWAS
Contribution of an additive locus to genetic variance when inheritance is multi-factorial with implications on interpretation of GWAS
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DOI：
10.1007/s00122-013-2064-2
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发表时间：
2013-06-01
影响因子：
5.4
通讯作者：
Verrier, Etienne
中科院分区：
文献类型：
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作者：
Gianola, Daniel;Hospital, Frederic;Verrier, Etienne
尽管连锁不平衡（LD）对遗传方差分配的影响已在数量遗传学中受到关注，但很少有人讨论这种现象如何影响给定基因座的方差归因。本文强调了这样的观点，即当存在连锁 LD 时，用于评估基因座对方差的贡献的标准指标可能会产生误导，并且基因座上效应和等位基因频率的分布或频率依赖性效应的存在等因素也会发挥作用。提出了一种明显新的度量标准，用于测量当 LD 存在时，基因座贡献了多少变异性。通过假设的模拟场景说明了干预因素的影响，例如 LD 的类型和范围、基因座数量、效应分布和基因座上的等位基因频率，以及生成频率依赖性效应的模型。讨论了对全基因组关联研究 (GWAS) 解释的影响，该研究通常在人类遗传学中进行，其中单标记回归和单一数量性状基因座 (QTL) 的假设很常见。结论是，当性状复杂且受到连锁不平衡中的许多基因组影响时，GWAS 分析中单个 QTL 贡献的标准变异归因可能在概念上和统计上具有误导性。在“遗传性缺失”传奇中还要考虑的另一个因素是什么？
Although the effects of linkage disequilibrium (LD) on partition of genetic variance have received attention in quantitative genetics, there has been little discussion on how this phenomenon affects attribution of variance to a given locus. This paper reinforces the point that standard metrics used for assessing the contribution of a locus to variance can be misleading when there is linkage LD and that factors such as distribution of effects and of allelic frequencies over loci, or existence of frequency-dependent effects, play a role as well. An apparently new metric is proposed for measuring how much of the variability is contributed by a locus when LD exists. Effects of intervening factors, such as type and extent of LD, number of loci, distribution of effects, and of allelic frequencies over loci, as well as a model for generating frequency-dependent effects, are illustrated via hypothetical simulation scenarios. Implications on the interpretation of genome-wide association studies (GWAS), as typically carried out in human genetics, where single marker regression and the assumption of a sole quantitative trait locus (QTL) are common, are discussed. It is concluded that the standard attributions to variance contributed by a single QTL from a GWAS analysis may be misleading, conceptually and statistically, when a trait is complex and affected by sets of many genes in linkage disequilibrium. Yet another factor to consider in the "missing heritability" saga?.