X-chromosome methylation patterns in females with multiple sclerosis
- 1Hunter Medical Research Institute
Abstract
Multiple sclerosis (MS) is approximately three times more common in females than in males, but sex-linked epigenetic mechanisms remain incompletely understood. We tested whether X-chromosome DNA methylation differs in females with MS and whether associated sites preferentially map to genes normally subject to X-chromosome inactivation (XCI). An X-chromosome-focused epigenome-wide association study was performed in whole blood from three datasets comprising 496 females with MS and 509 female controls, with independent evaluation in isolated CD4+ T cells (80 cases, 76 controls). At FDR < 0.01, 3 182 X-chromosome CpGs were hypomethylated in MS (mean {Delta}{beta} = -0.035). Hypomethylated CpGs were strongly enriched in non-escape genes normally subject to XCI relative to escape genes (OR 6.77; p = 1.55x10) and mapped to immune and chromatin-related processes. Exploratory cis-mQTL analysis identified strong local genetic effects at a small subset of loci, including WAS, IRAK1 and TLR7. In CD4+ T cells, 2 080 of the 3 182 whole-blood hypomethylated CpGs (65.4%) were also significantly hypomethylated. These findings identify a reproducible X-chromosome hypomethylation signature in female MS and support direct investigation of inactive-X regulation, XCI escape and X-linked immune gene dosage.
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BibTeX
@misc{calnin2026xchromosome,
title = {{X-chromosome methylation patterns in females with multiple sclerosis}},
author = {T. Calnin and V. E. Maltby and S. M. Burnard and A. Xavier and S. Simpson-Yap and I. van der Mei and S. Broadley and B. V. Taylor and H. Butzkueven and A.-L. Ponsonby and R. J. Scott and M. Jagodic and V. G. Jokubaitis and J. Lechner-Scott and R. A. Lea},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.26365261},
url = {https://www.medrxiv.org/content/10.64898/2026.10.13.26365261v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - X-chromosome methylation patterns in females with multiple sclerosis
AU - T. Calnin
AU - V. E. Maltby
AU - S. M. Burnard
AU - A. Xavier
AU - S. Simpson-Yap
AU - I. van der Mei
AU - S. Broadley
AU - B. V. Taylor
AU - H. Butzkueven
AU - A.-L. Ponsonby
AU - R. J. Scott
AU - M. Jagodic
AU - V. G. Jokubaitis
AU - J. Lechner-Scott
AU - R. A. Lea
PY - 2026
DA - 2026/10/13
PB - medRxiv
DO - 10.64898/2026.10.13.26365261
UR - https://www.medrxiv.org/content/10.64898/2026.10.13.26365261v1
AB - Multiple sclerosis (MS) is approximately three times more common in females than in males, but sex-linked epigenetic mechanisms remain incompletely understood. We tested whether X-chromosome DNA methylation differs in females with MS and whether associated sites preferentially map to genes normally subject to X-chromosome inactivation (XCI). An X-chromosome-focused epigenome-wide association study was performed in whole blood from three datasets comprising 496 females with MS and 509 female controls, with independent evaluation in isolated CD4+ T cells (80 cases, 76 controls). At FDR < 0.01, 3 182 X-chromosome CpGs were hypomethylated in MS (mean {Delta}{beta} = -0.035). Hypomethylated CpGs were strongly enriched in non-escape genes normally subject to XCI relative to escape genes (OR 6.77; p = 1.55x10) and mapped to immune and chromatin-related processes. Exploratory cis-mQTL analysis identified strong local genetic effects at a small subset of loci, including WAS, IRAK1 and TLR7. In CD4+ T cells, 2 080 of the 3 182 whole-blood hypomethylated CpGs (65.4%) were also significantly hypomethylated. These findings identify a reproducible X-chromosome hypomethylation signature in female MS and support direct investigation of inactive-X regulation, XCI escape and X-linked immune gene dosage.
ER -