Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease

作者：Tianxiao Huan, Roby Joehanes, Ci Song, Fen Peng, Yichen Guo, Michael Mendelson, Chen Yao, Chunyu Liu, Jiantao Ma, Melissa A. Richard, Golareh Agha, Weihua Guan, Lynn M. Almli, Karen N. Conneely, Joshua A. Keefe, Shih-Jen Hwang, Andrew D. Johnson, Myriam Fornage, Liming Liang, Daniel Levy · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-12228-z · 被引用次数：255 · 研究领域：Epigenetics and DNA Methylation、RNA modifications and cancer、Genetic Associations and Epidemiology

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.