Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease
Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease
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DOI：
10.1038/s41467-019-12228-z
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发表时间：
2019-09-19
影响因子：
16.6
通讯作者：
Leyy, Daniel
中科院分区：
文献类型：
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作者：
Huan, Tianxiao;Joehanes, Roby;Leyy, Daniel
鉴定甲基化数量性状位点（meqtl）并将其与来自全基因组关联研究（GWAS）的疾病相关变异整合，可能阐明遗传变异与疾病关联的功能机制。在这里，我们对来自4170个个体的全血中> 41.5万个CpG甲基化位点进行了GWAS，并绘制了470万个针对>12万个CpG的顺式和63万个反式meqtl变异。对来自两项研究的1347名参与者进行了独立的重复研究。通过将顺式meqtl变异与心血管疾病（CVD）性状的GWAS结果联系起来，我们通过孟德尔随机化分析确定了92个CVD性状的推定因果CpGs。进一步整合基因表达数据揭示了顺式cpg转录对与CVD有因果关系的证据。此外，我们确定了22个反式meqtl热点，每个热点靶向超过30个CpGs，并发现反式meqtl热点似乎顺式作用于附近转录调控基因的表达。我们的发现提供了强大的meQTL资源，并阐明了DNA甲基化与人类疾病的关系。
Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.