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Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation

Author

Listed:
  • René Luijk

    (Leiden University Medical Center)

  • Haoyu Wu

    (Leiden University Medical Center)

  • Cavin K Ward-Caviness

    (Helmholtz Zentrum München)

  • Eilis Hannon

    (University of Exeter Medical School)

  • Elena Carnero-Montoro

    (King’s College London
    Pfizer - University of Granada - Andalusian Government Center for Genomics and Oncological Research (GENYO))

  • Josine L. Min

    (University of Bristol
    University of Bristol)

  • Pooja Mandaviya

    (Erasmus University Medical Center
    Erasmus University Medical Center)

  • Martina Müller-Nurasyid

    (partner site: Munich Heart Alliance
    Helmholtz Zentrum München - German Research Center for Environmental Health
    Ludwig-Maximilians-University)

  • Hailiang Mei

    (Leiden University Medical Center)

  • Silvere M. Maarel

    (Leiden University Medical Center)

  • Caroline Relton

    (University of Bristol)

  • Jonathan Mill

    (University of Exeter Medical School)

  • Melanie Waldenberger

    (Helmholtz Zentrum München
    Helmholtz Zentrum München)

  • Jordana T. Bell

    (King’s College London)

  • Rick Jansen

    (Neuroscience Campus Amsterdam)

  • Alexandra Zhernakova

    (University Medical Centre Groningen)

  • Lude Franke

    (University Medical Centre Groningen)

  • Peter A. C. ‘t Hoen

    (Leiden University Medical Center)

  • Dorret I. Boomsma

    (Neuroscience Campus Amsterdam)

  • Cornelia M. Duijn

    (Genetic Epidemiology Unit, ErasmusMC)

  • Marleen M. J. Greevenbroek

    (Maastricht University Medical Center
    Maastricht University Medical Center)

  • Jan H. Veldink

    (University Medical Center Utrecht)

  • Cisca Wijmenga

    (University Medical Centre Groningen)

  • Joyce Meurs

    (Erasmus University Medical Center)

  • Lucia Daxinger

    (Leiden University Medical Center)

  • P. Eline Slagboom

    (Leiden University Medical Center)

  • Erik W. Zwet

    (Leiden University Medical Center)

  • Bastiaan T. Heijmans

    (Leiden University Medical Center)

Abstract

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.

Suggested Citation

  • René Luijk & Haoyu Wu & Cavin K Ward-Caviness & Eilis Hannon & Elena Carnero-Montoro & Josine L. Min & Pooja Mandaviya & Martina Müller-Nurasyid & Hailiang Mei & Silvere M. Maarel & Caroline Relton & , 2018. "Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05714-3
    DOI: 10.1038/s41467-018-05714-3
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