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 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 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.

FundersFunder number
Dutch Government
State of Bavaria
Wellcome Trust102215/2/13/2
Medical Research CouncilMC_UU_12013/2, MC_UU_00011/5
Biotechnology and Biological Sciences Research CouncilBB/I025263/1
Economic and Social Research CouncilES/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 Onderzoek184.033.111, 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)

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