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; 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

doi:10.1038/s41467-018-05714-3

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 DeelenEttje 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 Journal › Article › Academic › peer-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 language	English
Article number	3738
Pages (from-to)	1-9
Number of pages	9
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05714-3
Publication status	Published - 14 Sept 2018

Funding

This research was financially supported by several institutions: BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO, numbers 184.021.007 and 184.033.111); the UK Medical Research Council; Wellcome (www.wellcome.ac.uk; [grant number 102215/2/13/2 to ALSPAC]); the University of Bristol to ALSPAC; the UK Economic and Social Research Council (www.esrc.ac.uk; [ES/N000498/1] to CR); the UK Medical Research Council (www.mrc.ac.uk; grant numbers [MC_UU_12013/1, MC_UU_12013/2 to JLM, CR]); the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria; the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinno-vativ; the Wellcome Trust, Medical Research Council, European Union (EU), and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. Samples were contributed by LifeLines, the Leiden Longevity Study, the Netherlands Twin Registry (NTR), the Rotterdam Study, the Genetic Research in Isolated Populations program, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study, the Prospective ALS study Netherlands (PAN), Avon Longitudinal Study of Parents and Children (ALSPAC), International Schizophrenia Consortium, Cooperative Health Research in the Ausburg Region (KORA), TwinsUK. We thank the participants of all aforementioned biobanks and acknowledge the contributions of the investigators to this study. This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative.

Funders	Funder number
Dutch Government
State of Bavaria
Wellcome Trust	102215/2/13/2
Medical Research Council	MC_UU_12013/2, MC_UU_00011/5
Biotechnology and Biological Sciences Research Council	BB/I025263/1
Economic and Social Research Council	ES/N000498/1, MC_UU_12013/1
National Institute for Health and Care Research
European Commission
University of Bristol
Bundesministerium für Bildung und Forschung
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	184.033.111, 184.021.007
Deutsches Forschungszentrum für Gesundheit und Umwelt, Helmholtz Zentrum München
Münchner Zentrum für Gesundheitswissenschaften, Ludwig-Maximilians-Universität München

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-018-05714-3

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Luijk, R., Wu, H., Ward-Caviness, C. K., Hannon, E., Carnero-Montoro, E., Min, J. L., Mandaviya, P., Müller-Nurasyid, M., Mei, H., van der Maarel, S. M., Beekman, M., der Breggen, R. V., Deelen, J., Lakenberg, N., Moed, M., Suchiman, H. E. D., Arindrarto, W., van’t Hof, P., Jan Bonder, M., ... BIOS Consortium (2018). Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation. Nature Communications, 9(1), 1-9. Article 3738. https://doi.org/10.1038/s41467-018-05714-3

@article{5788248ba11544b5885dce6bb860af1a,

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

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.",

author = "Ren{\'e} Luijk and Haoyu Wu and Ward-Caviness, {Cavin K.} and Eilis Hannon and Elena Carnero-Montoro and Min, {Josine L.} and Pooja Mandaviya and Martina M{\"u}ller-Nurasyid and Hailiang Mei and {van der Maarel}, {Silvere M.} and Marian Beekman and {der Breggen}, {Ruud van} and Joris Deelen and Nico Lakenberg and Matthijs Moed and Suchiman, {H. Eka D.} and Wibowo Arindrarto and {van{\textquoteright}t Hof}, Peter and {Jan Bonder}, Marc and Patrick Deelen and Tigchelaar, {Ettje F.} and Alexandra Zhernakova and Zhernakova, {Dasha V.} and Jenny van Dongen and Hottenga, {Jouke J.} and Ren{\'e} Pool and Aaron Isaacs and Hofman, {Bert A.} and Mila Jhamai and {van der Kallen}, {Carla J.H.} and Schalkwijk, {Casper G.} and Stehouwer, {Coen D.A.} and {van den Berg}, {Leonard H.} and Michiel van Galen and Martijn Vermaat and Jeroen van Rooij and Uitterlinden, {Andr{\'e} G.} and Michael Verbiest and Marijn Verkerk and Kielbasa, {P. Szymon M.} and Jan Bot and Irene Nooren and Freerk van Dijk and Swertz, {Morris A.} and Diana van Heemst and Caroline Relton and Jonathan Mill and Melanie Waldenberger and Bell, {Jordana T.} and Rick Jansen and D.I. Boomsma and {BIOS Consortium}",

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month = sep,

day = "14",

doi = "10.1038/s41467-018-05714-3",

language = "English",

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journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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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

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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UR - http://www.scopus.com/inward/citedby.url?scp=85053315812&partnerID=8YFLogxK

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 -

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

Abstract

Funding

Cohort Studies

UN SDGs

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