Heritability of skewed X-inactivation in female twins is tissue-specific and associated with age

Antonino Zito, Matthew N. Davies, Pei Chien Tsai, Susanna Roberts, Rosa Andres-Ejarque, Stefano Nardone, Jordana T. Bell, Chloe C.Y. Wong, Kerrin S. Small*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

40 Scopus citations


Female somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes. Skewed XCI toward one parental X has been observed in several complex human traits, but the extent to which genetics and environment influence skewed XCI is largely unexplored. To address this, we quantify XCI-skew in multiple tissues and immune cell types in a twin cohort. Within an individual, XCI-skew differs between blood, fat and skin tissue, but is shared across immune cell types. XCI skew increases with age in blood, but not other tissues, and is associated with smoking. XCI-skew is increased in twins with Rheumatoid Arthritis compared to unaffected identical co-twins. XCI-skew is heritable in blood of females >55 years old (h2 = 0.34), but not in younger individuals or other tissues. This results in a Gene x Age interaction that shifts the functional dosage of all X-linked heterozygous loci in a tissue-restricted manner.

Original languageEnglish
Article number5339
JournalNature Communications
Issue number1
StatePublished - 01 12 2019

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© 2019, The Author(s).


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