Detecting DNA methylation patterns suggestive of variable escape from X-chromosome inactivation

Zhao, Q.; Bezerra, O. C. L.; Oros Klein, K.; Lamin, M.; Beaulieu, M.-C.; Rodger, M.; Kovacs, M.; O'Neil, L.; Brown, C. J.; Hudson, M.; Colmegna, I.; Bernatksy, S.; Gagnon, F.; Naumova, A. K.; Zhang, Q.; Greenwood, C. M.

doi:10.64898/2026.06.15.732395

bioRxiv · 10.64898/2026.06.15.732395

Detecting DNA methylation patterns suggestive of variable escape from X-chromosome inactivation

Zhao, Q.·Bezerra, O. C. L.·Oros Klein, K.·Lamin, M.·Beaulieu, M.-C.·Rodger, M.·Kovacs, M.·O'Neil, L.·Brown, C. J.·Hudson, M.·Colmegna, I.·Bernatksy, S.·Gagnon, F.·Naumova, A. K.·Zhang, Q.·Greenwood, C. M.

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Abstract

The X chromosome is often excluded from studies analyzing associations between traits and DNA methylation. In females, one copy of most genes on the X is inactivated (X-chromosome inactivation; XCI) through DNA methylation of the gene promoter on the inactive X. This leads to challenges in analyzing and interpreting DNA methylation data patterns. Particularly for sex-biased diseases and traits, there may be many loci of interest on the X chromosome, which contains about 5% of the genome. To address the need for appropriate analysis of DNA methylation data on the X chromosome, we develop a statistical approach to infer locus-specific escape from XCI sensitive to phenotype or covariate values. Performance of this method is illustrated by analysis of data from two sex-biased traits: rheumatoid arthritis which is 3-fold more common in females, and recurrent venous thromboembolism which occurs 2.5 times more often in males. Analyses of these two datasets identify new trait-associated loci on the X chromosome, demonstrate the capabilities of the new method for both bisulfite sequencing data and Illumina EPIC data, suggest at least one locus where variable escape may explain a sex-specific disease association, and rule out variable escape as a potential explanation at other loci. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=176 HEIGHT=200 SRC="FIGDIR/small/732395v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@108c23aorg.highwire.dtl.DTLVardef@77dc0org.highwire.dtl.DTLVardef@1d105d0org.highwire.dtl.DTLVardef@1d4b543_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender (bioRender.com)

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Zhao, Q., Bezerra, O. C. L., Oros Klein, K., Lamin, M., Beaulieu, M.-C., Rodger, M., Kovacs, M., O'Neil, L., Brown, C. J., Hudson, M., Colmegna, I., Bernatksy, S., Gagnon, F., Naumova, A. K., Zhang, Q., Greenwood, C. M.. 2026-06-19. Detecting DNA methylation patterns suggestive of variable escape from X-chromosome inactivation. https://doi.org/10.64898/2026.06.15.732395

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