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Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome

Author

Listed:
  • Tina Roostaei

    (Columbia University Irving Medical Center)

  • Hans-Ulrich Klein

    (Columbia University Irving Medical Center)

  • Yiyi Ma

    (Columbia University Irving Medical Center)

  • Daniel Felsky

    (University of Toronto)

  • Pia Kivisäkk

    (Massachusetts General Hospital)

  • Sarah M. Connor

    (Columbia University Irving Medical Center)

  • Alexandra Kroshilina

    (Columbia University Irving Medical Center)

  • Christina Yung

    (Columbia University Irving Medical Center)

  • Belinda J. Kaskow

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Xiaorong Shao

    (University of California)

  • Brooke Rhead

    (University of California)

  • José M. Ordovás

    (Tufts University)

  • Devin M. Absher

    (HudsonAlpha Institute for Biotechnology)

  • Donna K. Arnett

    (University of Kentucky)

  • Jia Liu

    (City University of New York)

  • Nikolaos Patsopoulos

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Lisa F. Barcellos

    (University of California)

  • Howard L. Weiner

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Philip L. De Jager

    (Columbia University Irving Medical Center)

Abstract

Identifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4+ T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.

Suggested Citation

  • Tina Roostaei & Hans-Ulrich Klein & Yiyi Ma & Daniel Felsky & Pia Kivisäkk & Sarah M. Connor & Alexandra Kroshilina & Christina Yung & Belinda J. Kaskow & Xiaorong Shao & Brooke Rhead & José M. Ordová, 2021. "Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27427-w
    DOI: 10.1038/s41467-021-27427-w
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    References listed on IDEAS

    as
    1. Olivier Delaneau & Halit Ongen & Andrew A. Brown & Alexandre Fort & Nikolaos I. Panousis & Emmanouil T. Dermitzakis, 2017. "A complete tool set for molecular QTL discovery and analysis," Nature Communications, Nature, vol. 8(1), pages 1-7, August.
    2. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    3. Lara Kular & Yun Liu & Sabrina Ruhrmann & Galina Zheleznyakova & Francesco Marabita & David Gomez-Cabrero & Tojo James & Ewoud Ewing & Magdalena Lindén & Bartosz Górnikiewicz & Shahin Aeinehband & Per, 2018. "DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    4. Kyoko Watanabe & Erdogan Taskesen & Arjen Bochoven & Danielle Posthuma, 2017. "Functional mapping and annotation of genetic associations with FUMA," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
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