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 and Kerrin S. Small ()
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Antonino Zito: King’s College London
Matthew N. Davies: Ervaxx Limited
Pei-Chien Tsai: King’s College London
Susanna Roberts: King’s College London
Rosa Andres-Ejarque: King’s College London
Stefano Nardone: Harvard Medical School
Jordana T. Bell: King’s College London
Chloe C. Y. Wong: King’s College London
Kerrin S. Small: King’s College London

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13340-w

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