TY - JOUR
T1 - Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation
AU - Luijk, René
AU - Wu, Haoyu
AU - Ward-Caviness, Cavin K.
AU - Hannon, Eilis
AU - Carnero-Montoro, Elena
AU - Min, Josine L.
AU - Mandaviya, Pooja
AU - Müller-Nurasyid, Martina
AU - Mei, Hailiang
AU - van der Maarel, Silvere M.
AU - Beekman, Marian
AU - der Breggen, Ruud van
AU - Deelen, Joris
AU - Lakenberg, Nico
AU - Moed, Matthijs
AU - Suchiman, H. Eka D.
AU - Arindrarto, Wibowo
AU - van’t Hof, Peter
AU - Jan Bonder, Marc
AU - Deelen, Patrick
AU - Tigchelaar, Ettje F.
AU - Zhernakova, Alexandra
AU - Zhernakova, Dasha V.
AU - van Dongen, Jenny
AU - Hottenga, Jouke J.
AU - Pool, René
AU - Isaacs, Aaron
AU - Hofman, Bert A.
AU - Jhamai, Mila
AU - van der Kallen, Carla J.H.
AU - Schalkwijk, Casper G.
AU - Stehouwer, Coen D.A.
AU - van den Berg, Leonard H.
AU - van Galen, Michiel
AU - Vermaat, Martijn
AU - van Rooij, Jeroen
AU - Uitterlinden, André G.
AU - Verbiest, Michael
AU - Verkerk, Marijn
AU - Kielbasa, P. Szymon M.
AU - Bot, Jan
AU - Nooren, Irene
AU - van Dijk, Freerk
AU - Swertz, Morris A.
AU - van Heemst, Diana
AU - Relton, Caroline
AU - Mill, Jonathan
AU - Waldenberger, Melanie
AU - Bell, Jordana T.
AU - Jansen, Rick
AU - Boomsma, D.I.
AU - BIOS Consortium
PY - 2018/9/14
Y1 - 2018/9/14
N2 - 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.
AB - 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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U2 - 10.1038/s41467-018-05714-3
DO - 10.1038/s41467-018-05714-3
M3 - Article
C2 - 30218040
SN - 2041-1723
VL - 9
SP - 1
EP - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3738
ER -
