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

• DOI: 10.1038/s41467-018-05714-3
• Publication Date: 2018-09-10T08:26:13Z
• Authors: René Luijk; Haoyu Wu; Cavin K Ward-Cavi...; Eilis Hannon; Elena Carnero-Mon...; Josine L. Min; Pooja Mandaviya; Martina Müller-Nu...; Hailiang Mei; Silvere M. van de...; ; Marian Beekman; Ruud van der Breggen; Joris Deelen; Nico Lakenberg; Matthijs Moed; H. Eka D. Suchiman; Wibowo Arindrarto; Peter van’t Hof; Marc Jan Bonder; Patrick Deelen; Ettje F. Tigchelaar; Alexandra Zhernakova; Dasha V. Zhernakova; Jenny van Dongen; Jouke J. Hottenga; René Pool; Aaron Isaacs; Bert A. Hofman; Mila Jhamai; Carla J. H. van d...; Casper G. Schalkwijk; Coen D. A. Stehouwer; Leonard H. van de...; Michiel van Galen; Martijn Vermaat; Jeroen van Rooij; André G. Uitterli...; Michael Verbiest; Marijn Verkerk; P. Szymon M. Kiel...; Jan Bot; Irene Nooren; Freerk van Dijk; Morris A. Swertz; Diana van Heemst; 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. van D...; Marleen M. J. van...; Jan H. Veldink; Cisca Wijmenga; Joyce van Meurs; Lucia Daxinger; P. Eline Slagboom; Erik W. van Zwet; Bastiaan T. Heijmans
• Keywords: EXPRESSION; Netherlands Twin Register (NTR); Male; 0301 basic medicine; EMC NIHES-01-64-02; Chromosomal Proteins, Non-Histone; Science; Ubiquitin-Protein Ligases; 610; Gene Expression; LINKED GENE; Article; Methyltransferases/genetics; Tripartite Motif Proteins; 03 medical and health sciences; X Chromosome Inactivation/genetics; X Chromosome Inactivation; HUMAN GENOME; Humans; gamma-Globins; Ubiquitin-Protein Ligases/genetics; SDG 14 - Life Below Water; HISTONE H3; gamma-Globins/genetics; SMCHD1; Gene Expression Profiling; OBJECTIVES; Q; Genetic Variation; Methyltransferases; DNA Methylation; ROTTERDAM; EPIGENOMES; Chromosomal Proteins; DNA-Binding Proteins; VARIABILITY; Non-Histone/genetics; EMC MM-01-39-09-A; CpG Islands; Female; CLUSTERS; Tripartite Motif Proteins/genetics; DNA-Binding Proteins/genetics; DNA Methylation/genetics

AbstractX-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.