Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05714-3
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Funding
- BBMRI-NL
- Dutch government (NWO) [184.021.007, 184.033.111]
- UK Medical Research Council
- Wellcome [102215/2/13/2]
- University of Bristol
- UK Economic and Social Research Council [ES/N000498/1]
- UK Medical Research Council [MC_UU_12013/1, MC_UU_12013/2]
- Helmholtz Zentrum Munchen - German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
- State of Bavaria
- Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat as part of LMUinnovativ
- Wellcome Trust
- Medical Research Council
- European Union (EU)
- National Institute for Health Research (NIHR)
- King's College London
- SURF Cooperative
- BBSRC [BB/I025263/1] Funding Source: UKRI
- ESRC [ES/N000404/1] Funding Source: UKRI
- MRC [MC_UU_00011/5, MC_UU_12013/2] Funding Source: UKRI
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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, similar to 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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