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Nat Commun. 2019 Sep 19;10(1):4267. doi: 10.1038/s41467-019-12228-z.

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

Huan T1,2, Joehanes R3,4, Song C3,4,5,6, Peng F7, Guo Y8,9, Mendelson M3,4,10, Yao C3,4, Liu C11, Ma J3,4, Richard M7, Agha G12, Guan W13, Almli LM14, Conneely KN15, Keefe J3,4, Hwang SJ3,4, Johnson AD3,4, Fornage M7, Liang L16,17, Levy D18,19.

Author information

1
The Framingham Heart Study, Framingham, MA, USA. tianxiao.huan@nih.gov.
2
The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. tianxiao.huan@nih.gov.
3
The Framingham Heart Study, Framingham, MA, USA.
4
The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
5
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
6
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
7
Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
8
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
9
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
10
Department of Cardiology, Boston Children's Hospital, Harvard University, Boston, MA, USA.
11
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
12
Mailman School of Public Health, Columbia University, New York City, NY, USA.
13
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
14
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
15
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
16
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. lliang@hsph.harvard.edu.
17
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. lliang@hsph.harvard.edu.
18
The Framingham Heart Study, Framingham, MA, USA. Levyd@nih.gov.
19
The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Levyd@nih.gov.

Abstract

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.

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