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

Research output: Contribution to journalArticle

BIOS Consortium, 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 van der Maarel, Caroline Relton, Jonathan Mill, Melanie Waldenberger, Jordana T Bell, Rick Jansen, Alexandra Zhernakova, Lude Franke, Peter A C 't Hoen, Dorret I Boomsma & 9 more Cornelia M van Duijn, Marleen M J van Greevenbroek, Jan H Veldink, Cisca Wijmenga, Joyce van Meurs, Lucia Daxinger, P Eline Slagboom, Erik W van Zwet, Bastiaan T Heijmans

Original languageEnglish
Pages (from-to)3738
JournalNature Communications
Issue number1
Accepted/In press23 Jul 2018
Published14 Sep 2018

King's Authors


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.

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