Exploratory analysis of age and sex dependent DNA methylation patterns on the X-chromosome in whole blood samples

Shuxia Li, Jesper Lund, Kaare Christensen, Jan Baumbach, Jonas Mengel-From, Torben A Kruse, Weilong Li, Afsaneh Mohammadnejad, Alison Pattie, Riccardo E Marioni, Ian J Deary, Qihua Tan*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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BACKGROUND: Large numbers of autosomal sites are found differentially methylated in the aging genome. Due to analytical difficulties in dealing with sex differences in X-chromosome content and X-inactivation (XCI) in females, this has not been explored for the X chromosome. METHODS: Using data from middle age to elderly individuals (age 55+ years) from two Danish cohorts of monozygotic twins and the Scottish Lothian Birth Cohort 1921, we conducted an X-chromosome-wide analysis of age-associated DNA methylation patterns with consideration of stably inferred XCI status. RESULTS: Through analysing and comparing sex-specific X-linked DNA methylation changes over age late in life, we identified 123, 293 and 55 CpG sites significant (FDR < 0.05) only in males, only in females and in both sexes of Danish twins. All findings were significantly replicated in the two Danish twin cohorts. CpG sites escaping XCI are predominantly de-methylated with increasing age across cohorts. In contrast, CpGs highly methylated in both sexes are methylated even further with increasing age. Among the replicated sites in Danish samples, 16 (13%), 24 (8.2%) and 3 (5.5%) CpGs were further validated in LBC1921 (FDR < 0.05). CONCLUSIONS: The X-chromosome of whole blood leukocytes displays age- and sex-dependent DNA methylation patterns in relation to XCI across cohorts.

Original languageEnglish
Article number39
JournalGenome Medicine
Issue number39
Number of pages13
Publication statusPublished - 28. Apr 2020


  • Aging; DNA methylation; Twins; Whole blood; X-chromosome; X-inactivation
  • Whole blood
  • X-inactivation
  • Aging
  • DNA methylation
  • X-chromosome
  • Twins


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