Systematic identification of genetic influences on methylation across the human life course.
Systematic identification of genetic influences on methylation across the human life course.
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DOI：
10.1186/s13059-016-0926-z
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发表时间：
2016-03-31
期刊：
影响因子：
12.3
通讯作者：
Relton CL
中科院分区：
文献类型：
--
作者：
Gaunt TR;Shihab HA;Hemani G;Min JL;Woodward G;Lyttleton O;Zheng J;Duggirala A;McArdle WL;Ho K;Ring SM;Evans DM;Davey Smith G;Relton CL
遗传变异对复杂疾病的影响可能是通过一系列高度动态的表观遗传过程来调节的，这些过程在发育和以后的生命中表现出时间上的变化。在这里，我们介绍了人类血液中五个不同生命阶段对DNA甲基化(甲基化数量性状基因座(MQTL))的遗传影响目录：出生时的儿童、儿童、青春期及其母亲怀孕和中年。我们表明，甲基化的遗传效应在整个生命过程中高度稳定，并且甲基化变异的遗传贡献的发育变化主要是通过环境或随机效应的增加而发生的。虽然我们定位了很大一部分顺式作用的遗传变异，但影响甲基化的遗传效应中有更大的组成部分是反式作用的。然而，在已发现的mQTL中，只有7%是反式效应，这表明反式成分是高度多基因的。最后，我们估计了mQTL对复杂性状变异的贡献，并推断甲基化可能具有符合无限小模型的因果作用，在该模型中，许多甲基化位点每个都有很小的影响，但总体贡献很大。DNA甲基化包含一个重要的可遗传成分，在整个生命周期中保持一致。我们的结果表明，甲基化的遗传成分可能在复杂的性状中起到因果作用。本文介绍的mQTL数据库为那些有兴趣研究甲基化在疾病中的作用的人提供了丰富的资源。本文的在线版本(doi：10.1186/s13059-0160926-z)包含补充材料，授权用户可以使用。
The influence of genetic variation on complex diseases is potentially mediated through a range of highly dynamic epigenetic processes exhibiting temporal variation during development and later life. Here we present a catalogue of the genetic influences on DNA methylation (methylation quantitative trait loci (mQTL)) at five different life stages in human blood: children at birth, childhood, adolescence and their mothers during pregnancy and middle age. We show that genetic effects on methylation are highly stable across the life course and that developmental change in the genetic contribution to variation in methylation occurs primarily through increases in environmental or stochastic effects. Though we map a large proportion of the cis-acting genetic variation, a much larger component of genetic effects influencing methylation are acting in trans. However, only 7 % of discovered mQTL are trans-effects, suggesting that the trans component is highly polygenic. Finally, we estimate the contribution of mQTL to variation in complex traits and infer that methylation may have a causal role consistent with an infinitesimal model in which many methylation sites each have a small influence, amounting to a large overall contribution. DNA methylation contains a significant heritable component that remains consistent across the lifespan. Our results suggest that the genetic component of methylation may have a causal role in complex traits. The database of mQTL presented here provide a rich resource for those interested in investigating the role of methylation in disease. The online version of this article (doi:10.1186/s13059-016-0926-z) contains supplementary material, which is available to authorized users.