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

Author

Listed:
  • Tianxiao Huan

    (The Framingham Heart Study
    National Heart, Lung, and Blood Institute, National Institutes of Health)

  • Roby Joehanes

    (The Framingham Heart Study
    National Heart, Lung, and Blood Institute, National Institutes of Health)

  • Ci Song

    (The Framingham Heart Study
    National Heart, Lung, and Blood Institute, National Institutes of Health
    Uppsala University
    Uppsala University)

  • Fen Peng

    (University of Texas Health Science Center at Houston)

  • Yichen Guo

    (Harvard University
    Harvard University)

  • Michael Mendelson

    (The Framingham Heart Study
    National Heart, Lung, and Blood Institute, National Institutes of Health
    Harvard University)

  • Chen Yao

    (The Framingham Heart Study
    National Heart, Lung, and Blood Institute, National Institutes of Health)

  • Chunyu Liu

    (Boston University School of Public Health)

  • Jiantao Ma

    (The Framingham Heart Study
    National Heart, Lung, and Blood Institute, National Institutes of Health)

  • Melissa Richard

    (University of Texas Health Science Center at Houston)

  • Golareh Agha

    (Columbia University)

  • Weihua Guan

    (University of Minnesota)

  • Lynn M. Almli

    (Emory University School of Medicine)

  • Karen N. Conneely

    (Emory University School of Medicine)

  • Joshua Keefe

    (The Framingham Heart Study
    National Heart, Lung, and Blood Institute, National Institutes of Health)

  • Shih-Jen Hwang

    (The Framingham Heart Study
    National Heart, Lung, and Blood Institute, National Institutes of Health)

  • Andrew D. Johnson

    (The Framingham Heart Study
    National Heart, Lung, and Blood Institute, National Institutes of Health)

  • Myriam Fornage

    (University of Texas Health Science Center at Houston)

  • Liming Liang

    (Harvard University
    Harvard T.H. Chan School of Public Health)

  • Daniel Levy

    (The Framingham Heart Study
    National Heart, Lung, and Blood Institute, National Institutes of 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.

Suggested Citation

  • Tianxiao Huan & Roby Joehanes & Ci Song & Fen Peng & Yichen Guo & Michael Mendelson & Chen Yao & Chunyu Liu & Jiantao Ma & Melissa Richard & Golareh Agha & Weihua Guan & Lynn M. Almli & Karen N. Conne, 2019. "Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12228-z
    DOI: 10.1038/s41467-019-12228-z
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    Cited by:

    1. Lulu Shang & Wei Zhao & Yi Zhe Wang & Zheng Li & Jerome J. Choi & Minjung Kho & Thomas H. Mosley & Sharon L. R. Kardia & Jennifer A. Smith & Xiang Zhou, 2023. "meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Matthias Wielscher & Pooja R. Mandaviya & Brigitte Kuehnel & Roby Joehanes & Rima Mustafa & Oliver Robinson & Yan Zhang & Barbara Bodinier & Esther Walton & Pashupati P. Mishra & Pascal Schlosser & Ro, 2022. "DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Caibo Ning & Linyun Fan & Meng Jin & Wenji Wang & Zhiqiang Hu & Yimin Cai & Liangkai Chen & Zequn Lu & Ming Zhang & Can Chen & Yanmin Li & Fuwei Zhang & Wenzhuo Wang & Yizhuo Liu & Shuoni Chen & Yuan , 2023. "Genome-wide association analysis of left ventricular imaging-derived phenotypes identifies 72 risk loci and yields genetic insights into hypertrophic cardiomyopathy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Gemma Cadby & Corey Giles & Phillip E. Melton & Kevin Huynh & Natalie A. Mellett & Thy Duong & Anh Nguyen & Michelle Cinel & Alex Smith & Gavriel Olshansky & Tingting Wang & Marta Brozynska & Mike Ino, 2022. "Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Adrienne Tin & Pascal Schlosser & Pamela R. Matias-Garcia & Chris H. L. Thio & Roby Joehanes & Hongbo Liu & Zhi Yu & Antoine Weihs & Anselm Hoppmann & Franziska Grundner-Culemann & Josine L. Min & Vic, 2021. "Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus," Nature Communications, Nature, vol. 12(1), pages 1-18, December.

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