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

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, Jonathan Mill, Melanie Waldenberger, Jordana T. Bell, Rick Jansen, Alexandra Zhernakova, Lude Franke, Peter A. C. ‘t Hoen, Dorret I. Boomsma, Cornelia M. Duijn, Marleen M. J. Greevenbroek, Jan H. Veldink, Cisca Wijmenga, Joyce Meurs, Lucia Daxinger, P. Eline Slagboom, Erik W. Zwet and Bastiaan T. Heijmans ()
Additional contact information
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
Josine L. Min: University of Bristol
Pooja Mandaviya: Erasmus University Medical Center
Martina Müller-Nurasyid: partner site: Munich Heart Alliance
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
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
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

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05714-3

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