Pleiotropic Effects of Trait-Associated Genetic Variation on DNA Methylation: Utility for Refining GWAS Loci.
Pleiotropic Effects of Trait-Associated Genetic Variation on DNA Methylation: Utility for Refining GWAS Loci.
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DOI：
10.1016/j.ajhg.2017.04.013
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发表时间：
2017-06-01
影响因子：
9.8
通讯作者：
Mill J
中科院分区：
文献类型：
--
作者：
Hannon E;Weedon M;Bray N;O'Donovan M;Mill J
在复杂性状的全基因组关联研究（GWAS）中发现的大多数遗传变异被认为是通过影响基因调控而不是直接改变蛋白质产物来起作用的。因此，参与疾病的实际基因不一定是最接近相关变异的基因。通过整合来自GWAS分析的数据与来自调控变异的遗传学研究的数据，有可能鉴定与复杂性状和基因调控措施两者多效性相关的变体。在这项研究中，我们使用了基于汇总数据的孟德尔随机化（SMR），这是一种用于识别与复杂性状和基因表达多效性相关的变体的方法，用于识别与复杂性状和DNA甲基化相关的变体。我们使用从两种不同组织（血液和胎脑）生成的大型DNA甲基化数量性状基因座（mQTL）数据集，通过稳健的GWAS数据对>40个复杂性状的基因进行优先排序，并发现与使用表达QTL（eQTL）数据进行的SMR分析结果有相当大的重叠。我们确定了与一系列复杂性状的GWAS变体相关的可变DNA甲基化的多个例子，证明了这种方法用于细化遗传关联信号的实用性。
Most genetic variants identified in genome-wide association studies (GWASs) of complex traits are thought to act by affecting gene regulation rather than directly altering the protein product. As a consequence, the actual genes involved in disease are not necessarily the most proximal to the associated variants. By integrating data from GWAS analyses with those from genetic studies of regulatory variation, it is possible to identify variants pleiotropically associated with both a complex trait and measures of gene regulation. In this study, we used summary-data-based Mendelian randomization (SMR), a method developed to identify variants pleiotropically associated with both complex traits and gene expression, to identify variants associated with complex traits and DNA methylation. We used large DNA methylation quantitative trait locus (mQTL) datasets generated from two different tissues (blood and fetal brain) to prioritize genes for >40 complex traits with robust GWAS data and found considerable overlap with the results of SMR analyses performed with expression QTL (eQTL) data. We identified multiple examples of variable DNA methylation associated with GWAS variants for a range of complex traits, demonstrating the utility of this approach for refining genetic association signals.