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. van der Maarel, 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 & 32 others 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 der Kallen, Casper G. Schalkwijk, Coen D.A. Stehouwer, Leonard H. van den Berg, Michiel van Galen, Martijn Vermaat, Jeroen van Rooij, André G. Uitterlinden, Michael Verbiest, Marijn Verkerk, P. Szymon M. Kielbasa, Jan Bot, Irene Nooren, Freerk van Dijk, Morris A. Swertz, Diana van Heemst, Caroline Relton, Jonathan Mill, Melanie Waldenberger, Jordana T. Bell, Rick Jansen, D.I. Boomsma, BIOS Consortium

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Article number3738
Pages (from-to)1-9
Number of pages9
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 14 Sep 2018

Fingerprint

X Chromosome Inactivation
methylation
chromosomes
DNA Methylation
Chromosomes
deactivation
deoxyribonucleic acid
genes
Genes
loci
X Chromosome
escape
Metagenomics
CpG Islands
Methylation
Alleles

Cite this

Luijk, R., Wu, H., Ward-Caviness, C. K., Hannon, E., Carnero-Montoro, E., Min, J. L., ... BIOS Consortium (2018). Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation. Nature Communications, 9(1), 1-9. [3738]. https://doi.org/10.1038/s41467-018-05714-3
Luijk, René ; Wu, Haoyu ; Ward-Caviness, Cavin K. ; Hannon, Eilis ; Carnero-Montoro, Elena ; Min, Josine L. ; Mandaviya, Pooja ; Müller-Nurasyid, Martina ; Mei, Hailiang ; van der Maarel, Silvere M. ; Beekman, Marian ; der Breggen, Ruud van ; Deelen, Joris ; Lakenberg, Nico ; Moed, Matthijs ; Suchiman, H. Eka D. ; Arindrarto, Wibowo ; van’t Hof, Peter ; Jan Bonder, Marc ; Deelen, Patrick ; Tigchelaar, Ettje F. ; Zhernakova, Alexandra ; Zhernakova, Dasha V. ; van Dongen, Jenny ; Hottenga, Jouke J. ; Pool, René ; Isaacs, Aaron ; Hofman, Bert A. ; Jhamai, Mila ; van der Kallen, Carla J.H. ; Schalkwijk, Casper G. ; Stehouwer, Coen D.A. ; van den Berg, Leonard H. ; van Galen, Michiel ; Vermaat, Martijn ; van Rooij, Jeroen ; Uitterlinden, André G. ; Verbiest, Michael ; Verkerk, Marijn ; Kielbasa, P. Szymon M. ; Bot, Jan ; Nooren, Irene ; van Dijk, Freerk ; Swertz, Morris A. ; van Heemst, Diana ; Relton, Caroline ; Mill, Jonathan ; Waldenberger, Melanie ; Bell, Jordana T. ; Jansen, Rick ; Boomsma, D.I. ; BIOS Consortium. / Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation. In: Nature Communications. 2018 ; Vol. 9, No. 1. pp. 1-9.
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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.",
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Luijk, R, Wu, H, Ward-Caviness, CK, Hannon, E, Carnero-Montoro, E, Min, JL, Mandaviya, P, Müller-Nurasyid, M, Mei, H, van der Maarel, SM, Beekman, M, der Breggen, RV, Deelen, J, Lakenberg, N, Moed, M, Suchiman, HED, Arindrarto, W, van’t Hof, P, Jan Bonder, M, Deelen, P, Tigchelaar, EF, Zhernakova, A, Zhernakova, DV, van Dongen, J, Hottenga, JJ, Pool, R, Isaacs, A, Hofman, BA, Jhamai, M, van der Kallen, CJH, Schalkwijk, CG, Stehouwer, CDA, van den Berg, LH, van Galen, M, Vermaat, M, van Rooij, J, Uitterlinden, AG, Verbiest, M, Verkerk, M, Kielbasa, PSM, Bot, J, Nooren, I, van Dijk, F, Swertz, MA, van Heemst, D, Relton, C, Mill, J, Waldenberger, M, Bell, JT, Jansen, R, Boomsma, DI & BIOS Consortium 2018, 'Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation' Nature Communications, vol. 9, no. 1, 3738, pp. 1-9. https://doi.org/10.1038/s41467-018-05714-3

Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation. / Luijk, René; Wu, Haoyu; Ward-Caviness, Cavin K.; Hannon, Eilis; Carnero-Montoro, Elena; Min, Josine L.; Mandaviya, Pooja; Müller-Nurasyid, Martina; Mei, Hailiang; van der Maarel, Silvere M.; Beekman, Marian; der Breggen, Ruud van; Deelen, Joris; Lakenberg, Nico; Moed, Matthijs; Suchiman, H. Eka D.; Arindrarto, Wibowo; van’t Hof, Peter; Jan Bonder, Marc; Deelen, Patrick; Tigchelaar, Ettje F.; Zhernakova, Alexandra; Zhernakova, Dasha V.; van Dongen, Jenny; Hottenga, Jouke J.; Pool, René; Isaacs, Aaron; Hofman, Bert A.; Jhamai, Mila; van der Kallen, Carla J.H.; Schalkwijk, Casper G.; Stehouwer, Coen D.A.; van den Berg, Leonard H.; van Galen, Michiel; Vermaat, Martijn; van Rooij, Jeroen; Uitterlinden, André G.; Verbiest, Michael; Verkerk, Marijn; Kielbasa, P. Szymon M.; Bot, Jan; Nooren, Irene; van Dijk, Freerk; Swertz, Morris A.; van Heemst, Diana; Relton, Caroline; Mill, Jonathan; Waldenberger, Melanie; Bell, Jordana T.; Jansen, Rick; Boomsma, D.I.; BIOS Consortium.

In: Nature Communications, Vol. 9, No. 1, 3738, 14.09.2018, p. 1-9.

Research output: Contribution to JournalArticleAcademicpeer-review

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

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SP - 1

EP - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

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