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

• Type of Material: Article
• Authors: Tianxiao Huan, Framingham Heart Study; Roby Joehanes, Framingham Heart Study; Ci Song, Framingham Heart Study; Fen Peng, University of Texas Health Science Center; Yichen Guo, Harvard University; Michael Mendelson, Framingham Heart Study; Chen Yao, Framingham Heart Study; Chunyu Liu, Boston University; Jiantao Ma, Framingham Heart Study; Melissa Richard, University of Texas Health Science Center; Golareh Agha, Columbia University; Weihua Guan, University of Minnesota; Lynn M. Almli, Emory University; Karen N Conneely, Emory University; Joshua Keefe, Framingham Heart Study; Shih-Jen Hwang, Framingham Heart Study; Andrew D. Johnson, Framingham Heart Study; Myriam Fornage, University of Texas Health Science Center; Liming Liang, Harvard University; Daniel Leyy, Framingham Heart Study
• Language: English
• Date: 2019-09-19
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-019-12228-z
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 10
• Issue: 1
• Start Page: 4267
• End Page: 4267
• Grant/Funding Information: The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195 and HHSN268201500001I.; The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health.; The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute; and the Center for Information Technology, National Institutes of Health, Bethesda,MD; Dr. Ci Song is supported by the international postdoc fellowship award from Swedish Research Council (2016-00598).; M.M.M. is supported by a NHLBI K99HL136875.; The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I).; Funding was also supported by 5RC2HL102419 and R01NS087541.
• Keywords: SDCCAG8; MENDELIAN RANDOMIZATION; ASSOCIATION; PRESSURE; Science & Technology; Science & Technology - Other Topics; BODY-MASS INDEX; DESIGN; ARCHITECTURE; R PACKAGE; LOCI; HEART; Multidisciplinary Sciences
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics; Health Sciences, Public Health

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.